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Chuong CM, Wu P, Yu Z, Liang YC, Widelitz RB. Organizational principles of integumentary Organs: Maximizing Variations for Effective Adaptation. Dev Biol 2025:S0012-1606(25)00073-9. [PMID: 40113027 DOI: 10.1016/j.ydbio.2025.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 03/16/2025] [Accepted: 03/17/2025] [Indexed: 03/22/2025]
Abstract
The integument serves as the interface between an organism and its environment. It primarily comprises ectoderm-derived epithelium and mesenchyme derived from various embryonic sources. These integumentary organs serve as a barrier defining the physiological boundary between the internal and exterior environments and fulfill diverse functions. How does the integument generate such a large diversity? Here, we attempt to decipher the organizational principles. We focus on amniotes and use appendage follicles as the primary examples. The integument begins as a simple planar sheet of coupled epithelial and mesenchymal cells, then becomes more complex through the following patterning processes. 1) De novo Turing periodic patterning process: This process converts the integument into multiple skin appendage units. 2) Adaptive patterning process: Dermal muscle, blood vessels, adipose tissue, and other components are assembled and organized around appendage follicles when present. 3) Cyclic renewal: Skin appendage follicles contain stem cells and their niches, enabling physiological molting and regeneration in the adult animal. 4) Spatial variations: Multiple appendage units allow modulation of shape, size, keratin types, and color patterns of feathers and hairs across the animal's surface. 5) Temporal phenotypic plasticity: Cyclic renewal permits temporal transition of appendage phenotypes, i.e. regulatory patterning or integumentary metamorphosis, throughout an animal's lifetime. The diversities in (4) and (5) can be generated epigenetically within the same animal. Over the evolutionary timescale, different species can modulate the number, size, and distributions of existing ectodermal organs in the context of micro-evolution, allowing effective adaptation to new climates as seen in the variation of hair length among mammals. Novel ectodermal organs can also emerge in the context of macro-evolution, enabling animals to explore new ecological niches, as seen in the emergence of feathers on dinosaurs. These principles demonstrate how multi-scale organ adaption in the amniotes can maximize diverse and flexible integumentary organ phenotypes, producing a vast repertoire for natural selection and thereby providing effective adaptation and evolutionary advantages.
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Affiliation(s)
- Cheng Ming Chuong
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Ping Wu
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Zhou Yu
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Ya Chen Liang
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Randall B Widelitz
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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Castilla‐Ibeas A, Zdral S, Oberg KC, Ros MA. The limb dorsoventral axis: Lmx1b's role in development, pathology, evolution, and regeneration. Dev Dyn 2024; 253:798-814. [PMID: 38288855 PMCID: PMC11656695 DOI: 10.1002/dvdy.695] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 01/14/2024] [Accepted: 01/14/2024] [Indexed: 12/20/2024] Open
Abstract
The limb anatomy displays well-defined dorsal and ventral compartments, housing extensor, and flexor muscles, which play a crucial role in facilitating limb locomotion and manipulation. Despite its importance, the study of limb dorsoventral patterning has been relatively neglected compared to the other two axes leaving many crucial questions about the genes and developmental processes implicated unanswered. This review offers a thorough overview of the current understanding of limb dorsoventral patterning, synthesizing classical literature with recent research. It covers the specification of dorsal fate in the limb mesoderm and its subsequent translation into dorsal morphologies-a process directed by the transcription factor Lmx1b. We also discuss the potential role of dorsoventral patterning in the evolution of paired appendages and delve into the involvement of LMX1B in Nail-Patella syndrome, discussing the molecular and genetic aspects underlying this condition. Finally, the potential role of dorsoventral polarity in digit tip regeneration, a prominent instance of multi-tissue regeneration in mammals is also considered. We anticipate that this review will renew interest in a process that is critical to limb function and evolutionary adaptations but has nonetheless been overlooked.
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Affiliation(s)
- Alejandro Castilla‐Ibeas
- Department of Cellular and Molecular SignallingInstituto de Biotecnología y Biomedicina de Cantabria (IBBTEC), CSIC‐SODERCAN‐University of Cantabria)SantanderSpain
| | - Sofía Zdral
- Department of Cellular and Molecular SignallingInstituto de Biotecnología y Biomedicina de Cantabria (IBBTEC), CSIC‐SODERCAN‐University of Cantabria)SantanderSpain
| | - Kerby C. Oberg
- Department of Pathology and Human AnatomyLoma Linda University, School of MedicineLoma LindaCaliforniaUSA
| | - Marian A. Ros
- Department of Cellular and Molecular SignallingInstituto de Biotecnología y Biomedicina de Cantabria (IBBTEC), CSIC‐SODERCAN‐University of Cantabria)SantanderSpain
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Metzger BM, Özpolat BD. Developmental stage dependent effects of posterior and germline regeneration on sexual maturation in Platynereis dumerilii. Dev Biol 2024; 513:33-49. [PMID: 38797257 PMCID: PMC11211637 DOI: 10.1016/j.ydbio.2024.05.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 04/22/2024] [Accepted: 05/21/2024] [Indexed: 05/29/2024]
Abstract
Regeneration, regrowing lost and injured body parts, is an ability that generally declines with age or developmental transitions (i.e. metamorphosis, sexual maturation). Regeneration is also an energetically costly process, and trade-offs occur between regeneration and other costly processes such as growth, or sexual reproduction. Here we investigate the interplay of regeneration, reproduction, and developmental stage in the segmented worm Platynereis dumerilii. P. dumerilii can regenerate its whole posterior body axis, along with its reproductive cells, thereby having to carry out the two costly processes (somatic and germ cell regeneration) after injury. We specifically examine how developmental stage affects the success of germ cell regeneration and sexual maturation in developmentally young versus developmentally old organisms. We hypothesized that developmentally younger individuals (i.e. with gametes in early mitotic stages) will have higher regeneration success than the individuals at developmentally older stages (i.e. with gametes undergoing meiosis and maturation). Surprisingly, older amputated worms grew faster and matured earlier than younger amputees. To analyze germ cell regeneration during and after posterior regeneration, we used Hybridization Chain Reaction for the germline marker vasa. We found that regenerated worms start repopulating new segments with germ cell clusters as early as 14 days post amputation. In addition, vasa expression is observed in a wide region of newly-regenerated segments, which appears different from expression patterns during normal growth or regeneration in worms before gonial cluster expansion.
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Affiliation(s)
- Bria M Metzger
- Department of Biology, Washington University in St. Louis, One Brookings Drive, St. Louis, MO, 63130, USA; Eugene Bell Center for Regenerative Biology and Tissue Engineering, Marine Biological Laboratory, Woods Hole, MA, USA.
| | - B Duygu Özpolat
- Department of Biology, Washington University in St. Louis, One Brookings Drive, St. Louis, MO, 63130, USA; Eugene Bell Center for Regenerative Biology and Tissue Engineering, Marine Biological Laboratory, Woods Hole, MA, USA.
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4
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Youssef KK, Nieto MA. Epithelial-mesenchymal transition in tissue repair and degeneration. Nat Rev Mol Cell Biol 2024; 25:720-739. [PMID: 38684869 DOI: 10.1038/s41580-024-00733-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2024] [Indexed: 05/02/2024]
Abstract
Epithelial-mesenchymal transitions (EMTs) are the epitome of cell plasticity in embryonic development and cancer; during EMT, epithelial cells undergo dramatic phenotypic changes and become able to migrate to form different tissues or give rise to metastases, respectively. The importance of EMTs in other contexts, such as tissue repair and fibrosis in the adult, has become increasingly recognized and studied. In this Review, we discuss the function of EMT in the adult after tissue damage and compare features of embryonic and adult EMT. Whereas sustained EMT leads to adult tissue degeneration, fibrosis and organ failure, its transient activation, which confers phenotypic and functional plasticity on somatic cells, promotes tissue repair after damage. Understanding the mechanisms and temporal regulation of different EMTs provides insight into how some tissues heal and has the potential to open new therapeutic avenues to promote repair or regeneration of tissue damage that is currently irreversible. We also discuss therapeutic strategies that modulate EMT that hold clinical promise in ameliorating fibrosis, and how precise EMT activation could be harnessed to enhance tissue repair.
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Affiliation(s)
| | - M Angela Nieto
- Instituto de Neurociencias (CSIC-UMH), Sant Joan d'Alacant, Spain.
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.
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Huang L, Ho C, Ye X, Gao Y, Guo W, Chen J, Sun J, Wen D, Liu Y, Liu Y, Zhang Y, Li Q. Mechanisms and translational applications of regeneration in limbs: From renewable animals to humans. Ann Anat 2024; 255:152288. [PMID: 38823491 DOI: 10.1016/j.aanat.2024.152288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 04/08/2024] [Accepted: 05/27/2024] [Indexed: 06/03/2024]
Abstract
BACKGROUND The regenerative capacity of organisms declines throughout evolution, and mammals lack the ability to regenerate limbs after injury. Past approaches to achieving successful restoration through pharmacological intervention, tissue engineering, and cell therapies have faced significant challenges. OBJECTIVES This review aims to provide an overview of the current understanding of the mechanisms behind animal limb regeneration and the successful translation of these mechanisms for human tissue regeneration. RESULTS Particular attention was paid to the Mexican axolotl (Ambystoma mexicanum), the only adult tetrapod capable of limb regeneration. We will explore fundamental questions surrounding limb regeneration, such as how amputation initiates regeneration, how the limb knows when to stop and which parts to regenerate, and how these findings can apply to mammalian systems. CONCLUSIONS Given the urgent need for regenerative therapies to treat conditions like diabetic foot ulcers and trauma survivors, this review provides valuable insights and ideas for researchers, clinicians, and biomedical engineers seeking to facilitate the regeneration process or elicit full regeneration from partial regeneration events.
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Affiliation(s)
- Lu Huang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China; Department of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
| | - Chiakang Ho
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China
| | - Xinran Ye
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China
| | - Ya Gao
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China
| | - Weiming Guo
- Shanghai Key Laboratory of Stomatology, 639 Zhizaoju Road, Shanghai 200011, China; National Clinical Research Center for Oral Diseases, Shanghai 200011, China; National Center for Stomatology, Shanghai 200011, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai 200011, China; Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China
| | - Julie Chen
- Department of Ophthalmology, Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Jiaming Sun
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China
| | - Dongsheng Wen
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China
| | - Yangdan Liu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China
| | - Yuxin Liu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China
| | - Yifan Zhang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China.
| | - Qingfeng Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China.
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Fang X, Zhou J, Yang Y, Li D, Wang B. Integrating scRNA-seq and bulk RNA-seq to explore the differentiation mechanism of human nail stem cells mediated by onychofibroblasts. Front Cell Dev Biol 2024; 12:1416780. [PMID: 38887517 PMCID: PMC11181305 DOI: 10.3389/fcell.2024.1416780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 05/14/2024] [Indexed: 06/20/2024] Open
Abstract
Introduction: Nail stem cell (NSC) differentiation plays a vital role in maintaining nail homeostasis and facilitating digit regeneration. Recently, onychofibroblasts (OFs), specialized mesenchymal cells beneath the nail matrix, have emerged as potential regulators of NSC differentiation. However, limited understanding of OFs' cellular properties and transcriptomic profiles hinders our comprehension of their role. This study aims to characterize human OFs and investigate their involvement in NSC differentiation. Methods: Human OFs were isolated and characterized for their mesenchymal stem cell (MSC)-like phenotype through flow cytometry and multilineage differentiation assays. Bulk RNA-seq analysis was conducted on three samples of OFs and control fibroblasts from human nail units to delineate their molecular features. Integrated analysis with scRNA-seq data was performed to identify key signaling pathways involved in OF-induced NSC differentiation. Co-culture experiments, siRNA transfection, RT-qPCR, and immunocytochemistry were employed to investigate the effect of OF-derived soluble proteins on NSC differentiation. Drug treatments, RT-qPCR, western blotting, and immunocytochemistry were used to verify the regulation of candidate signaling pathways on NSC differentiation in vitro. Results: Human OFs exhibited slow cell cycle kinetics, expressed typical MSC markers, and demonstrated multilineage differentiation potential. Bulk RNA-seq analysis revealed differential gene expression in OFs compared to control fibroblasts, highlighting their role in coordinating nail development. Integrated analysis identified BMP4 as a pivotal signal for OFs to participate in NSC differentiation through mesenchymal-epithelial interactions, with the TGF-beta pathway possibly mediating this signal. OFs synthesized and secreted more BMP4 than control fibroblasts, and BMP4 derived from OFs induced NSC differentiation in a co-culture model. Recombinant human BMP4 activated the TGF-beta pathway in NSCs, leading to cell differentiation, while the BMP type I receptor inhibitor LDN193189 attenuated this effect. Discussion: This study characterizes the cellular and molecular features of human OFs, demonstrating their ability to regulate NSC differentiation via the TGF-beta signaling pathway. These findings establish a connection between the dermal microenvironment and NSC differentiation, suggesting the potential of OFs, in conjunction with NSCs, for developing novel therapies targeting nail and digit defects, even severe limb amputation.
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Affiliation(s)
- Xia Fang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Plastic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
| | - Jiateng Zhou
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Plastic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Yating Yang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dawei Li
- Department of Plastic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
| | - Bin Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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7
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Gupta I, Yeung J, Rahimi-Balaei M, Wu SR, Goldowitz D. Msx genes delineate a novel molecular map of the developing cerebellar neuroepithelium. Front Mol Neurosci 2024; 17:1356544. [PMID: 38742226 PMCID: PMC11089253 DOI: 10.3389/fnmol.2024.1356544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 04/12/2024] [Indexed: 05/16/2024] Open
Abstract
In the early cerebellar primordium, there are two progenitor zones, the ventricular zone (VZ) residing atop the IVth ventricle and the rhombic lip (RL) at the lateral edges of the developing cerebellum. These zones give rise to the several cell types that form the GABAergic and glutamatergic populations of the adult cerebellum, respectively. Recently, an understanding of the molecular compartmentation of these zones has emerged. To add to this knowledge base, we report on the Msx genes, a family of three transcription factors, that are expressed downstream of Bone Morphogenetic Protein (BMP) signaling in these zones. Using fluorescent RNA in situ hybridization, we have characterized the Msx (Msh Homeobox) genes and demonstrated that their spatiotemporal pattern segregates specific regions within the progenitor zones. Msx1 and Msx2 are compartmentalized within the rhombic lip (RL), while Msx3 is localized within the ventricular zone (VZ). The relationship of the Msx genes with an early marker of the glutamatergic lineage, Atoh1, was examined in Atoh1-null mice and it was found that the expression of Msx genes persisted. Importantly, the spatial expression of Msx1 and Msx3 altered in response to the elimination of Atoh1. These results point to the Msx genes as novel early markers of cerebellar progenitor zones and more importantly to an updated view of the molecular parcellation of the RL with respect to the canonical marker of the RL, Atoh1.
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Affiliation(s)
- Ishita Gupta
- British Columbia Children’s Hospital, Vancouver, BC, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Joanna Yeung
- British Columbia Children’s Hospital, Vancouver, BC, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Maryam Rahimi-Balaei
- British Columbia Children’s Hospital, Vancouver, BC, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Sih-Rong Wu
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
| | - Dan Goldowitz
- British Columbia Children’s Hospital, Vancouver, BC, Canada
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
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Kawasumi-Kita A, Lee SW, Ohtsuka D, Niimi K, Asakura Y, Kitajima K, Sakane Y, Tamura K, Ochi H, Suzuki KIT, Morishita Y. hoxc12/c13 as key regulators for rebooting the developmental program in Xenopus limb regeneration. Nat Commun 2024; 15:3340. [PMID: 38649703 PMCID: PMC11035627 DOI: 10.1038/s41467-024-47093-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 03/15/2024] [Indexed: 04/25/2024] Open
Abstract
During organ regeneration, after the initial responses to injury, gene expression patterns similar to those in normal development are reestablished during subsequent morphogenesis phases. This supports the idea that regeneration recapitulates development and predicts the existence of genes that reboot the developmental program after the initial responses. However, such rebooting mechanisms are largely unknown. Here, we explore core rebooting factors that operate during Xenopus limb regeneration. Transcriptomic analysis of larval limb blastema reveals that hoxc12/c13 show the highest regeneration specificity in expression. Knocking out each of them through genome editing inhibits cell proliferation and expression of a group of genes that are essential for development, resulting in autopod regeneration failure, while limb development and initial blastema formation are not affected. Furthermore, the induction of hoxc12/c13 expression partially restores froglet regenerative capacity which is normally very limited compared to larval regeneration. Thus, we demonstrate the existence of genes that have a profound impact alone on rebooting of the developmental program in a regeneration-specific manner.
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Affiliation(s)
- Aiko Kawasumi-Kita
- Laboratory for Developmental Morphogeometry, RIKEN Center for Biosystems Dynamics Research, Kobe, 650-0047, Japan
| | - Sang-Woo Lee
- Laboratory for Developmental Morphogeometry, RIKEN Center for Biosystems Dynamics Research, Kobe, 650-0047, Japan
| | - Daisuke Ohtsuka
- Laboratory for Developmental Morphogeometry, RIKEN Center for Biosystems Dynamics Research, Kobe, 650-0047, Japan
| | - Kaori Niimi
- Laboratory for Developmental Morphogeometry, RIKEN Center for Biosystems Dynamics Research, Kobe, 650-0047, Japan
| | - Yoshifumi Asakura
- Laboratory for Developmental Morphogeometry, RIKEN Center for Biosystems Dynamics Research, Kobe, 650-0047, Japan
| | - Keiichi Kitajima
- Laboratory for Developmental Morphogeometry, RIKEN Center for Biosystems Dynamics Research, Kobe, 650-0047, Japan
- Department of Ecological Developmental Adaptability Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, 980-8578, Japan
| | - Yuto Sakane
- Graduate School of Science, Hiroshima University, Higashihiroshima, Hiroshima, 739-8526, Japan
| | - Koji Tamura
- Department of Ecological Developmental Adaptability Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, 980-8578, Japan
| | - Haruki Ochi
- Institute for Promotion of Medical Science Research, Faculty of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata, 990-9585, Japan
| | - Ken-Ichi T Suzuki
- Graduate School of Science, Hiroshima University, Higashihiroshima, Hiroshima, 739-8526, Japan
- Emerging Model Organisms Facility, Trans-scale Biology Center, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki, Aichi, 444-8585, Japan
| | - Yoshihiro Morishita
- Laboratory for Developmental Morphogeometry, RIKEN Center for Biosystems Dynamics Research, Kobe, 650-0047, Japan.
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Tan FH, Bronner ME. Regenerative loss in the animal kingdom as viewed from the mouse digit tip and heart. Dev Biol 2024; 507:44-63. [PMID: 38145727 PMCID: PMC10922877 DOI: 10.1016/j.ydbio.2023.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 11/30/2023] [Accepted: 12/19/2023] [Indexed: 12/27/2023]
Abstract
The myriad regenerative abilities across the animal kingdom have fascinated us for centuries. Recent advances in developmental, molecular, and cellular biology have allowed us to unearth a surprising diversity of mechanisms through which these processes occur. Developing an all-encompassing theory of animal regeneration has thus proved a complex endeavor. In this chapter, we frame the evolution and loss of animal regeneration within the broad developmental constraints that may physiologically inhibit regenerative ability across animal phylogeny. We then examine the mouse as a model of regeneration loss, specifically the experimental systems of the digit tip and heart. We discuss the digit tip and heart as a positionally-limited system of regeneration and a temporally-limited system of regeneration, respectively. We delve into the physiological processes involved in both forms of regeneration, and how each phase of the healing and regenerative process may be affected by various molecular signals, systemic changes, or microenvironmental cues. Lastly, we also discuss the various approaches and interventions used to induce or improve the regenerative response in both contexts, and the implications they have for our understanding regenerative ability more broadly.
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Affiliation(s)
- Fayth Hui Tan
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - Marianne E Bronner
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
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10
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Noble A, Qubrosi R, Cariba S, Favaro K, Payne SL. Neural dependency in wound healing and regeneration. Dev Dyn 2024; 253:181-203. [PMID: 37638700 DOI: 10.1002/dvdy.650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 07/31/2023] [Accepted: 08/02/2023] [Indexed: 08/29/2023] Open
Abstract
In response to injury, humans and many other mammals form a fibrous scar that lacks the structure and function of the original tissue, whereas other vertebrate species can spontaneously regenerate damaged tissues and structures. Peripheral nerves have been identified as essential mediators of wound healing and regeneration in both mammalian and nonmammalian systems, interacting with the milieu of cells and biochemical signals present in the post-injury microenvironment. This review examines the diverse functions of peripheral nerves in tissue repair and regeneration, specifically during the processes of wound healing, blastema formation, and organ repair. We compare available evidence in mammalian and nonmammalian models, identifying critical nerve-mediated mechanisms for regeneration and providing future perspectives toward integrating these mechanisms into a therapeutic framework to promote regeneration.
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Affiliation(s)
- Alexandra Noble
- Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Rozana Qubrosi
- Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Solsa Cariba
- Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Kayla Favaro
- Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Samantha L Payne
- Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada
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11
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Metzger B, Özpolat BD. The cost and payout of age on germline regeneration and sexual maturation in Platynereis dumerilii. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.22.576726. [PMID: 38328233 PMCID: PMC10849560 DOI: 10.1101/2024.01.22.576726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Regeneration, regrowing lost and injured body parts, is an ability that generally declines with age or developmental transitions (i.e. metamorphosis, sexual maturation) in many organisms. Regeneration is also energetically a costly process, and trade-offs occur between regeneration and other costly processes such as somatic growth, or sexual reproduction. Here we investigate the interplay of regeneration, reproduction, and age in the segmented worm Platynereis dumerilii. P. dumerilii can regenerate its whole posterior body axis, along with its reproductive cells, thereby having to carry out the two costly processes (somatic and germ cell regeneration) after injury. We specifically examine how age affects the success of germ cell regeneration and sexual maturation in developmentally young versus old organisms. We hypothesized that developmentally younger individuals (i.e. lower investment state, with gametes in early mitotic stages) will have higher regeneration success and reach sexual maturation faster than the individuals at developmentally older stages (i.e. higher investment state, with gametes in the process of maturation). Surprisingly, older amputated worms grew faster and matured earlier than younger amputees, even though they had to regenerate more segments and recuperate the more costly germ cells which were already starting to undergo gametogenesis. To analyze germ cell regeneration across stages, we used Hybridization Chain Reaction for the germline marker vasa. We found that regenerated worms start repopulating new segments with germ cell clusters as early as 14 days post amputation. In addition, vasa expression is observed in a wide region of newly-regenerated segments, which appears different from expression patterns during normal growth or regeneration in worms before gonial cluster expansion. Future studies will focus on determining the exact sources of gonial clusters in regeneration.
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Affiliation(s)
- Bria Metzger
- Eugene Bell Center for Regenerative Biology and Tissue Engineering, Marine Biological Laboratory, Woods Hole, MA USA
- Department of Biology, Washington University in Saint Louis, MO, USA
- Currently at University of Washington, Seattle, WA, USA
| | - B Duygu Özpolat
- Eugene Bell Center for Regenerative Biology and Tissue Engineering, Marine Biological Laboratory, Woods Hole, MA USA
- Department of Biology, Washington University in Saint Louis, MO, USA
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12
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Xu C, Hutchins ED, Eckalbar W, Pendarvis K, Benson DM, Lake DF, McCarthy FM, Kusumi K. Comparative proteomic analysis of tail regeneration in the green anole lizard, Anolis carolinensis. NATURAL SCIENCES (WEINHEIM, GERMANY) 2024; 4:e20210421. [PMID: 38505006 PMCID: PMC10947082 DOI: 10.1002/ntls.20210421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/21/2024]
Abstract
As amniote vertebrates, lizards are the most closely related organisms to humans capable of appendage regeneration. Lizards can autotomize, or release their tails as a means of predator evasion, and subsequently regenerate a functional replacement. Green anoles (Anolis carolinensis) can regenerate their tails through a process that involves differential expression of hundreds of genes, which has previously been analyzed by transcriptomic and microRNA analysis. To investigate protein expression in regenerating tissue, we performed whole proteomic analysis of regenerating tail tip and base. This is the first proteomic data set available for any anole lizard. We identified a total of 2,646 proteins - 976 proteins only in the regenerating tail base, 796 only in the tail tip, and 874 in both tip and base. For over 90% of these proteins in these tissues, we were able to assign a clear orthology to gene models in either the Ensembl or NCBI databases. For 13 proteins in the tail base, 9 proteins in the tail tip, and 10 proteins in both regions, the gene model in Ensembl and NCBI matched an uncharacterized protein, confirming that these predictions are present in the proteome. Ontology and pathways analysis of proteins expressed in the regenerating tail base identified categories including actin filament-based process, ncRNA metabolism, regulation of phosphatase activity, small GTPase mediated signal transduction, and cellular component organization or biogenesis. Analysis of proteins expressed in the tail tip identified categories including regulation of organelle organization, regulation of protein localization, ubiquitin-dependent protein catabolism, small GTPase mediated signal transduction, morphogenesis of epithelium, and regulation of biological quality. These proteomic findings confirm pathways and gene families activated in tail regeneration in the green anole as well as identify uncharacterized proteins whose role in regrowth remains to be revealed. This study demonstrates the insights that are possible from the integration of proteomic and transcriptomic data in tail regrowth in the green anole, with potentially broader application to studies in other regenerative models.
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Affiliation(s)
- Cindy Xu
- School of Life Sciences, Arizona State University, Tempe, Arizona, USA
| | - Elizabeth D. Hutchins
- School of Life Sciences, Arizona State University, Tempe, Arizona, USA
- Current addresses: Translational Genomics Research Institute, Phoenix, Arizona, USA
| | - Walter Eckalbar
- School of Life Sciences, Arizona State University, Tempe, Arizona, USA
- Current addresses: School of Medicine, University of California, San Francisco, California, USA
| | - Ken Pendarvis
- Department of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, Arizona, USA
| | - Derek M. Benson
- School of Life Sciences, Arizona State University, Tempe, Arizona, USA
| | - Douglas F. Lake
- School of Life Sciences, Arizona State University, Tempe, Arizona, USA
| | - Fiona M. McCarthy
- Department of Animal and Comparative Biomedical Sciences, The University of Arizona, Tucson, Arizona, USA
| | - Kenro Kusumi
- School of Life Sciences, Arizona State University, Tempe, Arizona, USA
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13
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Wang J, Sun S, Deng H. Chemical reprogramming for cell fate manipulation: Methods, applications, and perspectives. Cell Stem Cell 2023; 30:1130-1147. [PMID: 37625410 DOI: 10.1016/j.stem.2023.08.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/31/2023] [Accepted: 08/01/2023] [Indexed: 08/27/2023]
Abstract
Chemical reprogramming offers an unprecedented opportunity to control somatic cell fate and generate desired cell types including pluripotent stem cells for applications in biomedicine in a precise, flexible, and controllable manner. Recent success in the chemical reprogramming of human somatic cells by activating a regeneration-like program provides an alternative way of producing stem cells for clinical translation. Likewise, chemical manipulation enables the capture of multiple (stem) cell states, ranging from totipotency to the stabilization of somatic fates in vitro. Here, we review progress in using chemical approaches for cell fate manipulation in addition to future opportunities in this promising field.
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Affiliation(s)
- Jinlin Wang
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China
| | - Shicheng Sun
- Changping Laboratory, 28 Life Science Park Road, Beijing, China; Murdoch Children's Research Institute, Royal Children's Hospital, Flemington Road, Parkville, VIC, Australia.
| | - Hongkui Deng
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; Changping Laboratory, 28 Life Science Park Road, Beijing, China.
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14
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Jou V, Lehoczky JA. Toeing the line between regeneration and fibrosis. Front Cell Dev Biol 2023; 11:1217185. [PMID: 37325560 PMCID: PMC10267333 DOI: 10.3389/fcell.2023.1217185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 05/23/2023] [Indexed: 06/17/2023] Open
Abstract
Understanding the remarkable capacity of vertebrates to naturally regenerate injured body parts has great importance for potential translation into human therapeutic applications. As compared to other vertebrates, mammals have low regenerative capacity for composite tissues like the limb. However, some primates and rodents can regenerate the distal tips of their digits following amputation, indicating that at least very distal mammalian limb tissues are competent for innate regeneration. It follows that successful digit tip regenerative outcome is highly dependent on the location of the amputation; those proximal to the position of the nail organ do not regenerate and result in fibrosis. This distal regeneration versus proximal fibrosis duality of the mouse digit tip serves as a powerful model to investigate the driving factors in determining each process. In this review, we present the current understanding of distal digit tip regeneration in the context of cellular heterogeneity and the potential for different cell types to function as progenitor cells, in pro-regenerative signaling, or in moderating fibrosis. We then go on to discuss these themes in the context of what is known about proximal digit fibrosis, towards generating hypotheses for these distinct healing processes in the distal and proximal mouse digit.
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Affiliation(s)
- Vivian Jou
- Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, United States
- Department of Orthopedic Surgery, Brigham and Women’s Hospital, Boston, MA, United States
| | - Jessica A. Lehoczky
- Department of Orthopedic Surgery, Brigham and Women’s Hospital, Boston, MA, United States
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15
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Abarca‐Buis RF, Krötzsch E. Proximal ear hole injury heals by limited regeneration during the early postnatal phase in mice. J Anat 2023; 242:402-416. [PMID: 36317926 PMCID: PMC9919478 DOI: 10.1111/joa.13782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 10/06/2022] [Accepted: 10/06/2022] [Indexed: 02/12/2023] Open
Abstract
Ear pinna is a particular feature of mammals that shows several repair responses depending on age. Two millimeter hole made in the pinna of middle-aged female mice heals due to partial reconstitution of new tissues (limited regeneration), whereas a hole punched in the ear of young mice forms a scar tissue. In these studies, the injury is made in the center of the ear pinna, but little is known about the type of reparative response along the proximodistal polarity of the ear. This study evaluated the effect of pinna polarity, age, and sex in the ear hole-repairing response in Balb/c mice. Proximal injuries were repaired more efficiently by limited regeneration than wounds made in the middle region. Non-injured ear histological analysis revealed a higher presence of muscle, adipose tissue, cartilage, and larger blood vessels in the proximal ear area, which could influence ear hole closure by limited regeneration. To evaluate the healing response during ear growth, we punched a standard hole in the proximal area of the ear on postnatal day 21 and 8-month-old mice (adults). Thirty-five days after the wound, both groups reached the same wound closure, despite the greater proportional size of holes made in the younger mice. Ear growth also improved ear hole closure in male mice. These results suggest that ear growth accelerates hole closure, providing an example of enhanced regenerative abilities in growing structures. Finally, hole closure kinetics in the growing ear indicated an early re-differentiation phase exhibited at 14 days post-wound. In conclusion, ear topography and growth positively influenced the healing response to ear holes, making it a tractable model to study in mammals.
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Affiliation(s)
- René Fernando Abarca‐Buis
- Laboratory of Connective Tissue, Centro Nacional de Investigación y Atención de QuemadosInstituto Nacional de Rehabilitación “Luís Guillermo Ibarra Ibarra”Ciudad de MéxicoMexico
| | - Edgar Krötzsch
- Laboratory of Connective Tissue, Centro Nacional de Investigación y Atención de QuemadosInstituto Nacional de Rehabilitación “Luís Guillermo Ibarra Ibarra”Ciudad de MéxicoMexico
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16
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Castilla-Ibeas A, Zdral S, Galán L, Haro E, Allou L, Campa VM, Icardo JM, Mundlos S, Oberg KC, Ros MA. Failure of digit tip regeneration in the absence of Lmx1b suggests Lmx1b functions disparate from dorsoventral polarity. Cell Rep 2023; 42:111975. [PMID: 36641754 DOI: 10.1016/j.celrep.2022.111975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 11/07/2022] [Accepted: 12/22/2022] [Indexed: 01/15/2023] Open
Abstract
Mammalian digit tip regeneration is linked to the presence of nail tissue, but a nail-explicit model is missing. Here, we report that nail-less double-ventral digits of ΔLARM1/2 mutants that lack limb-specific Lmx1b enhancers fail to regenerate. To separate the nail's effect from the lack of dorsoventral (DV) polarity, we also interrogate double-dorsal double-nail digits and show that they regenerate. Thus, DV polarity is not a prerequisite for regeneration, and the nail requirement is supported. Transcriptomic comparison between wild-type and non-regenerative ΔLARM1/2 mutant blastemas reveals differential upregulation of vascularization and connective tissue functional signatures in wild type versus upregulation of inflammation in the mutant. These results, together with the finding of Lmx1b expression in the postnatal dorsal dermis underneath the nail and uniformly in the regenerative blastema, open the possibility of additional Lmx1b roles in digit tip regeneration, in addition to the indirect effect of mediating the formation of the nail.
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Affiliation(s)
- Alejandro Castilla-Ibeas
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC; CSIC-SODERCAN-UC), Santander, Spain
| | - Sofía Zdral
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC; CSIC-SODERCAN-UC), Santander, Spain
| | - Laura Galán
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC; CSIC-SODERCAN-UC), Santander, Spain
| | - Endika Haro
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC; CSIC-SODERCAN-UC), Santander, Spain
| | - Lila Allou
- RG Development & Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Víctor M Campa
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC; CSIC-SODERCAN-UC), Santander, Spain
| | - Jose M Icardo
- Departamento de Anatomía y Biología Celular, Universidad de Cantabria, Santander, Spain
| | - Stefan Mundlos
- RG Development & Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Kerby C Oberg
- Department of Pathology and Human Anatomy, School of Medicine, Loma Linda University, Loma Linda, CA, USA
| | - Marian A Ros
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC; CSIC-SODERCAN-UC), Santander, Spain.
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17
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Aztekin C, Storer MA. To regenerate or not to regenerate: Vertebrate model organisms of regeneration-competency and -incompetency. Wound Repair Regen 2022; 30:623-635. [PMID: 35192230 PMCID: PMC7613846 DOI: 10.1111/wrr.13000] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/17/2022] [Accepted: 01/24/2022] [Indexed: 12/30/2022]
Abstract
Why only certain species can regenerate their appendages (e.g. tails and limbs) remains one of the biggest mysteries of nature. Unlike anuran tadpoles and salamanders, humans and other mammals cannot regenerate their limbs, but can only regrow lost digit tips under specific circumstances. Numerous hypotheses have been postulated to explain regeneration-incompetency in mammals. By studying model organisms that show varying regenerative abilities, we now have more opportunities to uncover what contributes to regeneration-incompetency and functionally test which perturbations restore appendage regrowth. Particularly, Xenopus laevis tail and limb, and mouse digit tip model systems exhibit naturally occurring variations in regenerative capacities. Here, we discuss major hypotheses that are suggested to contribute to regeneration-incompetency, and how species with varying regenerative abilities reflect on these hypotheses.
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Affiliation(s)
- Can Aztekin
- School of Life SciencesSwiss Federal Institute of Technology Lausanne (EPFL)Lausanne
| | - Mekayla A. Storer
- Department of Physiology, Development and Neuroscience and Wellcome‐MRC Cambridge Stem Cell InstituteUniversity of CambridgeCambridge
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18
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Normal embryonic development and neonatal digit regeneration in mice overexpressing a stem cell factor, Sall4. PLoS One 2022; 17:e0267273. [PMID: 35482646 PMCID: PMC9049339 DOI: 10.1371/journal.pone.0267273] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 04/05/2022] [Indexed: 01/29/2023] Open
Abstract
Sall4 encodes a transcription factor and is known to participate in the pluripotency network of embryonic stem cells. Sall4 expression is known to be high in early stage post-implantation mouse embryos. During early post-gastrulation stages, Sall4 is highly expressed in the tail bud and distal limb buds, where progenitor cells are maintained in an undifferentiated status. The expression of Sall4 is rapidly downregulated during embryonic development. We previously demonstrated that Sall4 is required for limb and posterior axial skeleton development by conditional deletion of Sall4 in the T (Brachyury) lineage. To gain insight into Sall4 functions in embryonic development and postnatal digit regeneration, we genetically overexpressed Sall4 in the mesodermal lineage by the TCre transgene and a novel knockin allele of Rosa26-loxP-stop-loxP-Sall4. In significant contrast to severe defects by Sall4 loss of function reported in previous studies, overexpression of Sall4 resulted in normal morphology and pattern in embryos and neonates. The length of limb long bones showed subtle reduction in Sall4-overexpression mice. It is known that the digit tip of neonatal mice has level-specific regenerative ability after experimental amputation. We observed Sall4 expression in the digit tip by using a sensitive Sall4-LacZ knock-in reporter expression. Sall4 overexpression did not alter the regenerative ability of the terminal phalange that normally regenerates after amputation. Moreover, Sall4 overexpression did not confer regenerative ability to the second phalange that normally does not regenerate after amputation. These genetic experiments show that overexpression of Sall4 does not alter the development of the appendicular and axial skeleton, or neonatal digit regeneration. The results suggest that Sall4 acts as a permissive factor rather than playing an instructive role.
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19
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Guan J, Wang G, Wang J, Zhang Z, Fu Y, Cheng L, Meng G, Lyu Y, Zhu J, Li Y, Wang Y, Liuyang S, Liu B, Yang Z, He H, Zhong X, Chen Q, Zhang X, Sun S, Lai W, Shi Y, Liu L, Wang L, Li C, Lu S, Deng H. Chemical reprogramming of human somatic cells to pluripotent stem cells. Nature 2022; 605:325-331. [PMID: 35418683 DOI: 10.1038/s41586-022-04593-5] [Citation(s) in RCA: 194] [Impact Index Per Article: 64.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 03/01/2022] [Indexed: 12/17/2022]
Abstract
Cellular reprogramming can manipulate the identity of cells to generate the desired cell types1-3. The use of cell intrinsic components, including oocyte cytoplasm and transcription factors, can enforce somatic cell reprogramming to pluripotent stem cells4-7. By contrast, chemical stimulation by exposure to small molecules offers an alternative approach that can manipulate cell fate in a simple and highly controllable manner8-10. However, human somatic cells are refractory to chemical stimulation owing to their stable epigenome2,11,12 and reduced plasticity13,14; it is therefore challenging to induce human pluripotent stem cells by chemical reprogramming. Here we demonstrate, by creating an intermediate plastic state, the chemical reprogramming of human somatic cells to human chemically induced pluripotent stem cells that exhibit key features of embryonic stem cells. The whole chemical reprogramming trajectory analysis delineated the induction of the intermediate plastic state at the early stage, during which chemical-induced dedifferentiation occurred, and this process was similar to the dedifferentiation process that occurs in axolotl limb regeneration. Moreover, we identified the JNK pathway as a major barrier to chemical reprogramming, the inhibition of which was indispensable for inducing cell plasticity and a regeneration-like program by suppressing pro-inflammatory pathways. Our chemical approach provides a platform for the generation and application of human pluripotent stem cells in biomedicine. This study lays foundations for developing regenerative therapeutic strategies that use well-defined chemicals to change cell fates in humans.
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Affiliation(s)
- Jingyang Guan
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Guan Wang
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.,State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Jinlin Wang
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
| | - Zhengyuan Zhang
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Yao Fu
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Lin Cheng
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Gaofan Meng
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Yulin Lyu
- School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China
| | - Jialiang Zhu
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Yanqin Li
- Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yanglu Wang
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Shijia Liuyang
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Bei Liu
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Zirun Yang
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.,State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Huanjing He
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Xinxing Zhong
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.,State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Qijing Chen
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Xu Zhang
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Shicheng Sun
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Weifeng Lai
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Yan Shi
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Lulu Liu
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Lipeng Wang
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Cheng Li
- School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing, China
| | - Shichun Lu
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Institute of Hepatobiliary Surgery of Chinese PLA, Key Laboratory of Digital Hepatobiliary Surgery, PLA, Beijing, China.
| | - Hongkui Deng
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China. .,State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.
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20
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Dolan CP, Imholt F, Yang TJ, Bokhari R, Gregory J, Yan M, Qureshi O, Zimmel K, Sherman KM, Falck A, Yu L, Leininger E, Brunauer R, Suva LJ, Gaddy D, Dawson LA, Muneoka K. Mouse Digit Tip Regeneration Is Mechanical Load Dependent. J Bone Miner Res 2022; 37:312-322. [PMID: 34783092 PMCID: PMC9400037 DOI: 10.1002/jbmr.4470] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 10/12/2021] [Accepted: 11/08/2021] [Indexed: 12/15/2022]
Abstract
Amputation of the mouse digit tip results in blastema-mediated regeneration. In this model, new bone regenerates de novo to lengthen the amputated stump bone, resulting in a functional replacement of the terminal phalangeal element along with associated non-skeletal tissues. Physiological examples of bone repair, such as distraction osteogenesis and fracture repair, are well known to require mechanical loading. However, the role of mechanical loading during mammalian digit tip regeneration is unknown. In this study, we demonstrate that reducing mechanical loading inhibits blastema formation by attenuating bone resorption and wound closure, resulting in the complete inhibition of digit regeneration. Mechanical unloading effects on wound healing and regeneration are completely reversible when mechanical loading is restored. Mechanical unloading after blastema formation results in a reduced rate of de novo bone formation, demonstrating mechanical load dependence of the bone regenerative response. Moreover, enhancing the wound-healing response of mechanically unloaded digits with the cyanoacrylate tissue adhesive Dermabond improves wound closure and partially rescues digit tip regeneration. Taken together, these results demonstrate that mammalian digit tip regeneration is mechanical load-dependent. Given that human fingertip regeneration shares many characteristics with the mouse digit tip, these results identify mechanical load as a previously unappreciated requirement for de novo bone regeneration in humans. © 2021 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Connor P Dolan
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA.,DoD-VA Extremity Trauma and Amputation Center of Excellence, Bethesda, MD, USA.,Department of Surgery, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, Bethesda, MD, USA
| | - Felisha Imholt
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Tae-Jung Yang
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Rihana Bokhari
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Joshua Gregory
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Mingquan Yan
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Osama Qureshi
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Katherine Zimmel
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Kirby M Sherman
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Alyssa Falck
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Ling Yu
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Eric Leininger
- Department of Cell and Molecular Biology, School of Science and Engineering, Tulane University, New Orleans, LA, USA
| | - Regina Brunauer
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Larry J Suva
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Dana Gaddy
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Lindsay A Dawson
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Ken Muneoka
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA.,Department of Cell and Molecular Biology, School of Science and Engineering, Tulane University, New Orleans, LA, USA
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21
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Yu L, Lin YL, Yan M, Li T, Wu EY, Zimmel K, Qureshi O, Falck A, Sherman KM, Huggins SS, Hurtado DO, Suva LJ, Gaddy D, Cai J, Brunauer R, Dawson LA, Muneoka K. Hyaline cartilage differentiation of fibroblasts in regeneration and regenerative medicine. Development 2022; 149:274141. [PMID: 35005773 PMCID: PMC8917415 DOI: 10.1242/dev.200249] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 12/15/2021] [Indexed: 11/30/2022]
Abstract
Amputation injuries in mammals are typically non-regenerative; however, joint regeneration is stimulated by BMP9 treatment, indicating the presence of latent articular chondrocyte progenitor cells. BMP9 induces a battery of chondrogenic genes in vivo, and a similar response is observed in cultures of amputation wound cells. Extended cultures of BMP9-treated cells results in differentiation of hyaline cartilage, and single cell RNAseq analysis identified wound fibroblasts as BMP9 responsive. This culture model was used to identify a BMP9-responsive adult fibroblast cell line and a culture strategy was developed to engineer hyaline cartilage for engraftment into an acutely damaged joint. Transplanted hyaline cartilage survived engraftment and maintained a hyaline cartilage phenotype, but did not form mature articular cartilage. In addition, individual hypertrophic chondrocytes were identified in some samples, indicating that the acute joint injury site can promote osteogenic progression of engrafted hyaline cartilage. The findings identify fibroblasts as a cell source for engineering articular cartilage and establish a novel experimental strategy that bridges the gap between regeneration biology and regenerative medicine. Summary:In vivo articular cartilage regeneration serves as a model to develop novel approaches for engineering cartilage to repair damaged joints and identifies fibroblasts as a BMP9-inducible chondroprogenitor.
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Affiliation(s)
- Ling Yu
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Yu-Lieh Lin
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Mingquan Yan
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Tao Li
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, People's Republic of China
| | - Emily Y. Wu
- Dewpoint Therapeutics, 6 Tide Street, Suite 300, Boston, MA 02210, USA
| | - Katherine Zimmel
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Osama Qureshi
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Alyssa Falck
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Kirby M. Sherman
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Shannon S. Huggins
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Daniel Osorio Hurtado
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Larry J. Suva
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Dana Gaddy
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - James Cai
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Regina Brunauer
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Lindsay A. Dawson
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Ken Muneoka
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
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22
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Johnson GL, Lehoczky JA. Mammalian Digit Tip Regeneration: Moving from Phenomenon to Molecular Mechanism. Cold Spring Harb Perspect Biol 2022; 14:a040857. [PMID: 34312249 PMCID: PMC8725625 DOI: 10.1101/cshperspect.a040857] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
In this review, we present the current state of knowledge surrounding mammalian digit tip regeneration. We discuss the origin and formation of the blastema, a structure integral to digit tip regeneration, as well as recent insights driven by single-cell RNA sequencing into the molecular markers and cellular composition of the blastema. The digit tip is a composite of many different tissue types and we address what is known about the role of these separate tissues in regeneration of the whole digit tip. Specifically, we discuss the most extensively studied tissues in the digit tip: bone, nail epithelium, and peripheral nerves. We also address how known molecular pathways in limb development can inform research into digit tip regeneration. Overall, the mouse digit tip is an excellent model of complex mammalian regeneration that can provide insight into inducing regeneration in human tissues.
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Affiliation(s)
- Gemma L Johnson
- Department of Orthopedics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
- Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Jessica A Lehoczky
- Department of Orthopedics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA
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23
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Mascharak S, Talbott HE, Januszyk M, Griffin M, Chen K, Davitt MF, Demeter J, Henn D, Bonham CA, Foster DS, Mooney N, Cheng R, Jackson PK, Wan DC, Gurtner GC, Longaker MT. Multi-omic analysis reveals divergent molecular events in scarring and regenerative wound healing. Cell Stem Cell 2022; 29:315-327.e6. [DOI: 10.1016/j.stem.2021.12.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 07/01/2021] [Accepted: 12/22/2021] [Indexed: 02/01/2023]
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24
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Choudhury TZ, Majumdar U, Basu M, Garg V. Impact of maternal hyperglycemia on cardiac development: Insights from animal models. Genesis 2021; 59:e23449. [PMID: 34498806 PMCID: PMC8599640 DOI: 10.1002/dvg.23449] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 08/17/2021] [Accepted: 08/23/2021] [Indexed: 12/19/2022]
Abstract
Congenital heart disease (CHD) is the leading cause of birth defect-related death in infants and is a global pediatric health concern. While the genetic causes of CHD have become increasingly recognized with advances in genome sequencing technologies, the etiology for the majority of cases of CHD is unknown. The maternal environment during embryogenesis has a profound impact on cardiac development, and numerous environmental factors are associated with an elevated risk of CHD. Maternal diabetes mellitus (matDM) is associated with up to a fivefold increased risk of having an infant with CHD. The rising prevalence of diabetes mellitus has led to a growing interest in the use of experimental diabetic models to elucidate mechanisms underlying this associated risk for CHD. The purpose of this review is to provide a comprehensive summary of rodent models that are being used to investigate alterations in cardiac developmental pathways when exposed to a maternal diabetic setting and to summarize the key findings from these models. The majority of studies in the field have utilized the chemically induced model of matDM, but recent advances have also been made using diet based and genetic models. Each model provides an opportunity to investigate unique aspects of matDM and is invaluable for a comprehensive understanding of the molecular and cellular mechanisms underlying matDM-associated CHD.
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Affiliation(s)
- Talita Z. Choudhury
- Center for Cardiovascular Research and Heart Center, Nationwide Children’s Hospital, Columbus, OH 43205, United States
- Graduate Program in Molecular, Cellular and Developmental Biology, The Ohio State University, Columbus, OH 43210, United States
| | - Uddalak Majumdar
- Center for Cardiovascular Research and Heart Center, Nationwide Children’s Hospital, Columbus, OH 43205, United States
| | - Madhumita Basu
- Center for Cardiovascular Research and Heart Center, Nationwide Children’s Hospital, Columbus, OH 43205, United States
- Department of Pediatrics, The Ohio State University, Columbus, OH 43210, United States
| | - Vidu Garg
- Center for Cardiovascular Research and Heart Center, Nationwide Children’s Hospital, Columbus, OH 43205, United States
- Department of Pediatrics, The Ohio State University, Columbus, OH 43210, United States
- Department of Molecular Genetics, The Ohio State University, Columbus, OH 43210, United States
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25
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Srivastava M. Beyond Casual Resemblances: Rigorous Frameworks for Comparing Regeneration Across Species. Annu Rev Cell Dev Biol 2021; 37:415-440. [PMID: 34288710 DOI: 10.1146/annurev-cellbio-120319-114716] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The majority of animal phyla have species that can regenerate. Comparing regeneration across animals can reconstruct the molecular and cellular evolutionary history of this process. Recent studies have revealed some similarity in regeneration mechanisms, but rigorous comparative methods are needed to assess whether these resemblances are ancestral pathways (homology) or are the result of convergent evolution (homoplasy). This review aims to provide a framework for comparing regeneration across animals, focusing on gene regulatory networks (GRNs), which are substrates for assessing process homology. The homology of the wound-induced activation of Wnt signaling and of adult stem cells are discussed as examples of ongoing studies of regeneration that enable comparisons in a GRN framework. Expanding the study of regeneration GRNs in currently studied species and broadening taxonomic sampling for these approaches will identify processes that are unifying principles of regeneration biology across animals. These insights are important both for evolutionary studies of regeneration and for human regenerative medicine. Expected final online publication date for the Annual Review of Cell and Developmental Biology, Volume 37 is October 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Mansi Srivastava
- Department of Organismic and Evolutionary Biology and Museum of Comparative Zoology, Harvard University, Cambridge, Massachusetts 02138, USA;
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26
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Berthézène CD, Rabiller L, Jourdan G, Cousin B, Pénicaud L, Casteilla L, Lorsignol A. Tissue Regeneration: The Dark Side of Opioids. Int J Mol Sci 2021; 22:7336. [PMID: 34298954 PMCID: PMC8307464 DOI: 10.3390/ijms22147336] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/25/2021] [Accepted: 06/28/2021] [Indexed: 12/13/2022] Open
Abstract
Opioids are regarded as among the most effective analgesic drugs and their use for the management of pain is considered standard of care. Despite their systematic administration in the peri-operative period, their impact on tissue repair has been studied mainly in the context of scar healing and is only beginning to be documented in the context of true tissue regeneration. Indeed, in mammals, growing evidence shows that opioids direct tissue repair towards scar healing, with a loss of tissue function, instead of the regenerative process that allows for recovery of both the morphology and function of tissue. Here, we review recent studies that highlight how opioids may prevent a regenerative process by silencing nociceptive nerve activity and a powerful anti-inflammatory effect. These data open up new perspectives for inducing tissue regeneration and argue for opioid-restricted strategies for managing pain associated with tissue injury.
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Affiliation(s)
- Cécile Dromard Berthézène
- RESTORE Research Center, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, 31000 Toulouse, France; (C.D.B.); (G.J.); (B.C.); (L.P.); (L.C.)
| | - Lise Rabiller
- Alan Edwards Center for Research on Pain, Department of Physiology and Cell Information Systems, McGill University, Montreal, QC H3A 0G1, Canada;
| | - Géraldine Jourdan
- RESTORE Research Center, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, 31000 Toulouse, France; (C.D.B.); (G.J.); (B.C.); (L.P.); (L.C.)
| | - Béatrice Cousin
- RESTORE Research Center, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, 31000 Toulouse, France; (C.D.B.); (G.J.); (B.C.); (L.P.); (L.C.)
| | - Luc Pénicaud
- RESTORE Research Center, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, 31000 Toulouse, France; (C.D.B.); (G.J.); (B.C.); (L.P.); (L.C.)
| | - Louis Casteilla
- RESTORE Research Center, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, 31000 Toulouse, France; (C.D.B.); (G.J.); (B.C.); (L.P.); (L.C.)
| | - Anne Lorsignol
- RESTORE Research Center, INSERM, CNRS, EFS, ENVT, Université P. Sabatier, 31000 Toulouse, France; (C.D.B.); (G.J.); (B.C.); (L.P.); (L.C.)
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27
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Sader F, Roy S. Tgf-β superfamily and limb regeneration: Tgf-β to start and Bmp to end. Dev Dyn 2021; 251:973-987. [PMID: 34096672 DOI: 10.1002/dvdy.379] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 12/19/2022] Open
Abstract
Axolotls represent a popular model to study how nature solved the problem of regenerating lost appendages in tetrapods. Our work over many years focused on trying to understand how these animals can achieve such a feat and not end up with a scarred up stump. The Tgf-β superfamily represents an interesting family to target since they are involved in wound healing in adults and pattern formation during development. This family is large and comprises Tgf-β, Bmps, activins and GDFs. In this review, we present work from us and others on Tgf-β & Bmps and highlight interesting observations between these two sub-families. Tgf-β is important for the preparation phase of regeneration and Bmps for the redevelopment phase and they do not overlap with one another. We present novel data showing that the Tgf-β non-canonical pathway is also not active during redevelopment. Finally, we propose a molecular model to explain how Tgf-β and Bmps maintain distinct windows of expression during regeneration in axolotls.
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Affiliation(s)
- Fadi Sader
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada
| | - Stéphane Roy
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.,Department of Stomatology, Faculty of Dentistry, Université de Montréal, Montréal, Québec, Canada
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28
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Khyeam S, Lee S, Huang GN. Genetic, Epigenetic, and Post-Transcriptional Basis of Divergent Tissue Regenerative Capacities Among Vertebrates. ADVANCED GENETICS (HOBOKEN, N.J.) 2021; 2:e10042. [PMID: 34423307 PMCID: PMC8372189 DOI: 10.1002/ggn2.10042] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 05/02/2021] [Accepted: 05/03/2021] [Indexed: 12/29/2022]
Abstract
Regeneration is widespread across the animal kingdom but varies vastly across phylogeny and even ontogeny. Adult mammalian regeneration in most organs and appendages is limited, while vertebrates such as zebrafish and salamanders are able to regenerate various organs and body parts. Here, we focus on the regeneration of appendages, spinal cord, and heart - organs and body parts that are highly regenerative among fish and amphibian species but limited in adult mammals. We then describe potential genetic, epigenetic, and post-transcriptional similarities among these different forms of regeneration across vertebrates and discuss several theories for diminished regenerative capacity throughout evolution.
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Affiliation(s)
- Sheamin Khyeam
- Cardiovascular Research Institute and Department of PhysiologyUniversity of CaliforniaSan FranciscoCaliforniaUSA
- Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell ResearchUniversity of CaliforniaSan FranciscoCaliforniaUSA
| | - Sukjun Lee
- Cardiovascular Research Institute and Department of PhysiologyUniversity of CaliforniaSan FranciscoCaliforniaUSA
- Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell ResearchUniversity of CaliforniaSan FranciscoCaliforniaUSA
| | - Guo N. Huang
- Cardiovascular Research Institute and Department of PhysiologyUniversity of CaliforniaSan FranciscoCaliforniaUSA
- Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell ResearchUniversity of CaliforniaSan FranciscoCaliforniaUSA
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29
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Alibardi L. Regeneration in anamniotes was replaced by regengrow and scarring in amniotes after land colonization and the evolution of terrestrial biological cycles. Dev Dyn 2021; 251:1404-1413. [PMID: 33793005 DOI: 10.1002/dvdy.341] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/01/2021] [Accepted: 03/24/2021] [Indexed: 12/11/2022] Open
Abstract
An evolutionary hypothesis explaining failure of regeneration among vertebrates is presented. Regeneration derives from postembryonic processes present during the life cycles of fish and amphibians that include larval and metamorphic phases with broad organ reorganizations. Developmental programs imprinted in their genomes are re-utilized with variations also in adults for regeneration. When vertebrates colonized land adopting the amniotic egg, some genes driving larval changes, and metamorphosis were lost and new genes evolved, further limiting regeneration. These included neural inhibitors for maintaining complex nervous systems, behavior and various levels of intelligence, and adaptive immune cells. The latter, that in anamniotes are executioners of metamorphic reorganization, became intolerant to embryonic-oncofetal-antigens impeding organ regeneration, a process that requires de-differentiation of adult cells and/or expansion of stem cells where these early antigens are formed. The evolution of terrestrial lifecycles produced vertebrates with complex bodies but no longer capable to regenerate their organs, mainly repaired by regengrow. Efforts of regenerative medicine to improve healing in humans should determine the diverse developmental pathways evolved between anamniotes and amniotes before attempting genetic manipulations such as the introduction of "anamniote regenerative genes" in amniotes. This operation may determine alteration in amniote developmental programs leading to teratomes, cancer, or death.
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Affiliation(s)
- Lorenzo Alibardi
- Comparative Histolab Padova and Department of Biology, University of Bologna, Bologna, Italy
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30
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The Potential of Nail Mini-Organ Stem Cells in Skin, Nail and Digit Tips Regeneration. Int J Mol Sci 2021; 22:ijms22062864. [PMID: 33799809 PMCID: PMC7998429 DOI: 10.3390/ijms22062864] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/08/2021] [Accepted: 03/08/2021] [Indexed: 12/17/2022] Open
Abstract
Nails are highly keratinized skin appendages that exhibit continuous growth under physiological conditions and full regeneration upon removal. These mini-organs are maintained by two autonomous populations of skin stem cells. The fast-cycling, highly proliferative stem cells of the nail matrix (nail stem cells (NSCs)) predominantly replenish the nail plate. Furthermore, the slow-cycling population of the nail proximal fold (nail proximal fold stem cells (NPFSCs)) displays bifunctional properties by contributing to the peri-nail epidermis under the normal homeostasis and the nail structure upon injury. Here, we discuss nail mini-organ stem cells’ location and their role in skin and nail homeostasis and regeneration, emphasizing their importance to orchestrate the whole digit tip regeneration. Such endogenous regeneration capabilities are observed in rodents and primates. However, they are limited to the region adjacent to the nail’s proximal area, indicating the crucial role of nail mini-organ stem cells in digit restoration. Further, we explore the molecular characteristics of nail mini-organ stem cells and the critical role of the bone morphogenetic protein (BMP) and Wnt signaling pathways in homeostatic nail growth and digit restoration. Finally, we investigate the latest accomplishments in stimulating regenerative responses in regeneration-incompetent injuries. These pioneer results might open up new opportunities to overcome amputated mammalian digits and limbs’ regenerative failures in the future.
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31
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Elchaninov A, Sukhikh G, Fatkhudinov T. Evolution of Regeneration in Animals: A Tangled Story. Front Ecol Evol 2021. [DOI: 10.3389/fevo.2021.621686] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
The evolution of regenerative capacity in multicellular animals represents one of the most complex and intriguing problems in biology. How could such a seemingly advantageous trait as self-repair become consistently attenuated by the evolution? This review article examines the concept of the origin and nature of regeneration, its connection with the processes of embryonic development and asexual reproduction, as well as with the mechanisms of tissue homeostasis. The article presents a variety of classical and modern hypotheses explaining different trends in the evolution of regenerative capacity which is not always beneficial for the individual and notably for the species. Mechanistically, these trends are driven by the evolution of signaling pathways and progressive restriction of differentiation plasticity with concomitant advances in adaptive immunity. Examples of phylogenetically enhanced regenerative capacity are considered as well, with appropriate evolutionary reasoning for the enhancement and discussion of its molecular mechanisms.
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32
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Storer MA, Miller FD. Cellular and molecular mechanisms that regulate mammalian digit tip regeneration. Open Biol 2020; 10:200194. [PMID: 32993414 PMCID: PMC7536070 DOI: 10.1098/rsob.200194] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Digit tip regeneration is one of the few examples of true multi-tissue regeneration in an adult mammal. The key step in this process is the formation of the blastema, a transient proliferating cell mass that generates the different cell types of the digit to replicate the original structure. Failure to form the blastema results in a lack of regeneration and has been postulated to be the reason why mammalian limbs cannot regrow following amputation. Understanding how the blastema forms and functions will help us to determine what is required for mammalian regeneration to occur and will provide insights into potential therapies for mammalian tissue regeneration and repair. This review summarizes the cellular and molecular mechanisms that influence murine blastema formation and govern digit tip regeneration.
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Affiliation(s)
- Mekayla A Storer
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Canada M5G 1L7
| | - Freda D Miller
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Canada M5G 1L7.,Department of Molecular Genetics, University of Toronto, Toronto, Canada M5G 1A8.,Department of Physiology, University of Toronto, Toronto, Canada M5G 1A8.,Institute of Medical Sciences, University of Toronto, Toronto, Canada M5G 1A8
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33
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Cordeiro IR, Yu R, Tanaka M. Regulation of the limb shape during the development of the Chinese softshell turtles. Evol Dev 2020; 22:451-462. [PMID: 32906209 PMCID: PMC7757393 DOI: 10.1111/ede.12352] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 07/29/2020] [Accepted: 08/05/2020] [Indexed: 01/20/2023]
Abstract
Interdigital cell death is an important mechanism employed by amniotes to shape their limbs; inhibiting this process leads to the formation of webbed fingers, as seen in bats and ducks. The Chinese softshell turtle Pelodiscus sinensis (Reptilia: Testudines: Trionychidae) has a distinctive limb morphology: the anterior side of the limbs has partially webbed fingers with claw‐like protrusions, while the posterior fingers are completely enclosed in webbings. Here, P. sinensis embryos were investigated to gain insights on the evolution of limb‐shaping mechanisms in amniotes. We found cell death and cell senescence in their interdigital webbings. Spatial or temporal modulation of these processes were correlated with the appearance of indentations in the webbings, but not a complete regression of this tissue. No differences in interdigital cell proliferation were found. In subsequent stages, differential growth of the finger cartilages led to a major difference in limb shape. While no asymmetry in bone morphogenetic protein signaling was evident during interdigital cell death stages, some components of this pathway were expressed exclusively in the clawed digit tips, which also had earlier ossification. In addition, a delay and/or truncation in the chondrogenesis of the posterior digits was found in comparison with the anterior digits of P. sinensis, and also when compared with the previously published pattern of digit skeletogenesis of turtles without posterior webbings. In conclusion, modulation of cell death, as well as a heterochrony in digit chondrogenesis, may contribute to the formation of the unique limbs of the Chinese softshell turtles.
Cell death and senescence shape the interdigital webbings of Pelodiscus sinensis. Delayed chondrogenesis/ossification and truncated tips are found in posterior digits, as well as differential expression of bone morphogenetic proteins and Msh homeobox 1 transcription factors.
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Affiliation(s)
- Ingrid R Cordeiro
- Department of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan
| | - Reiko Yu
- Department of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan
| | - Mikiko Tanaka
- Department of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan
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34
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Alibardi L. Appendage regeneration in anamniotes utilizes genes active during larval-metamorphic stages that have been lost or altered in amniotes: The case for studying lizard tail regeneration. J Morphol 2020; 281:1358-1381. [PMID: 32865265 DOI: 10.1002/jmor.21251] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 07/20/2020] [Accepted: 07/25/2020] [Indexed: 12/17/2022]
Abstract
This review elaborates the idea that organ regeneration derives from specific evolutionary histories of vertebrates. Regenerative ability depends on genomic regulation of genes specific to the life-cycles that have differentially evolved in anamniotes and amniotes. In aquatic environments, where fish and amphibians live, one or multiple metamorphic transitions occur before the adult stage is reached. Each transition involves the destruction and remodeling of larval organs that are replaced with adult organs. After organ injury or loss in adult anamniotes, regeneration uses similar genes and developmental process than those operating during larval growth and metamorphosis. Therefore, the broad presence of regenerative capability across anamniotes is possible because generating new organs is included in their life history at metamorphic stages. Soft hyaluronate-rich regenerative blastemas grow in submersed or in hydrated environments, that is, essential conditions for regeneration, like during development. In adult anamniotes, the ability to regenerate different organs decreases in comparison to larval stages and becomes limited during aging. Comparisons of genes activated during metamorphosis and regeneration in anamniotes identify key genes unique to these processes, and include thyroid, wnt and non-coding RNAs developmental pathways. In the terrestrial environment, some genes or developmental pathways for metamorphic transitions were lost during amniote evolution, determining loss of regeneration. Among amniotes, the formation of soft and hydrated blastemas only occurs in lizards, a morphogenetic process that evolved favoring their survival through tail autotomy, leading to a massive although imperfect regeneration of the tail. Deciphering genes activity during lizard tail regeneration would address future attempts to recreate in other amniotes regenerative blastemas that grow into variably completed organs.
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Dawson LA, Schanes PP, Marrero L, Jordan K, Brunauer R, Zimmel KN, Qureshi O, Imholt FM, Falck AR, Yan M, Dolan CP, Yu L, Muneoka K. Proximal digit tip amputation initiates simultaneous blastema and transient fibrosis formation and results in partial regeneration. Wound Repair Regen 2020; 29:196-205. [PMID: 32815252 DOI: 10.1111/wrr.12856] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/09/2020] [Accepted: 07/23/2020] [Indexed: 12/14/2022]
Abstract
Complete extremity regeneration in mammals is restricted to distal amputations of the digit tip, the terminal phalanx (P3). In mice, P3 regeneration is mediated via the formation of a blastema, a transient population of progenitor cells that form from the blending of periosteal and endosteal/marrow compartmentalized cells that undergo differentiation to restore the amputated structures. Compartmentalized blastema cells are formed independently, and periosteal compartment-derived cells are required for restoration of amputated skeletal length. P3 regenerative capacity is progressively attenuated at increasingly more proximal amputation levels, eventually resulting in regenerative failure. The continuum of regenerative capacity within the P3 wound milieu is a unique model to investigate mammalian blastema formation in response to distal amputation, as well as the healing response associated with regenerative failure at proximal amputation levels. We report that P3 proximal amputation healing, previously reported to result in regenerative failure, is not an example of complete regenerative failure, but instead is characterized by a limited bone regeneration response restricted to the endosteal/marrow compartment. The regeneration response is mediated by blastema formation within the endosteal/marrow compartment, and blastemal osteogenesis progresses through intramembranous ossification in a polarized proximal to distal sequence. Unlike bone regeneration following distal P3 amputation, osteogenesis within the periosteal compartment is not observed in response to proximal P3 amputation. We provide evidence that proximal P3 amputation initiates the formation of fibrotic tissue that isolates the endosteal/marrow compartment from the periosteal compartment and wound epidermis. While the fibrotic response is transient and later resolved, these studies demonstrate that blastema formation and fibrosis can occur in close proximity, with the regenerative response dominating the final outcome. Moreover, the results suggest that the attenuated proximal P3 regeneration response is associated with the absence of periosteal-compartment participation in blastema formation and bone regeneration.
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Affiliation(s)
- Lindsay A Dawson
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA
| | - Paula P Schanes
- Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA
| | - Luis Marrero
- Department of Orthopedic Surgery, Louisiana State University School of Medicine, New Orleans, Louisiana, USA.,Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
| | - Kathryn Jordan
- Department of Orthopedic Surgery, Louisiana State University School of Medicine, New Orleans, Louisiana, USA.,Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.,College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Regina Brunauer
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA
| | - Katherine N Zimmel
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA
| | - Osama Qureshi
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA
| | - Felisha M Imholt
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA
| | - Alyssa R Falck
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA
| | - Mingquan Yan
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA
| | - Connor P Dolan
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA
| | - Ling Yu
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA
| | - Ken Muneoka
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA
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36
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Vincent E, Villiard E, Sader F, Dhakal S, Kwok BH, Roy S. BMP signaling is essential for sustaining proximo-distal progression in regenerating axolotl limbs. Development 2020; 147:dev.170829. [PMID: 32665245 DOI: 10.1242/dev.170829] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 06/30/2020] [Indexed: 02/04/2023]
Abstract
Amputation of a salamander limb triggers a regeneration process that is perfect. A limited number of genes have been studied in this context and even fewer have been analyzed functionally. In this work, we use the BMP signaling inhibitor LDN193189 on Ambystoma mexicanum to explore the role of BMPs in regeneration. We find that BMP signaling is required for proper expression of various patterning genes and that its inhibition causes major defects in the regenerated limbs. Fgf8 is downregulated when BMP signaling is blocked, but ectopic injection of either human or axolotl protein did not rescue the defects. By administering LDN193189 treatments at different time points during regeneration, we show clearly that limb regeneration progresses in a proximal to distal fashion. This demonstrates that BMPs play a major role in patterning of regenerated limbs and that regeneration is a progressive process like development.
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Affiliation(s)
- Etienne Vincent
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal, Québec, H3T 1J4, Canada
| | - Eric Villiard
- Department of Stomatology, Faculty of Dentistry, Université de Montréal, Montréal, Québec, H3T 1J4, Canada
| | - Fadi Sader
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal, Québec, H3T 1J4, Canada
| | - Sabin Dhakal
- Institute for Research in Immunology and Cancer (IRIC), Département de médecine, Université de Montréal, Montréal, H3T 1J4, Canada
| | - Benjamin H Kwok
- Institute for Research in Immunology and Cancer (IRIC), Département de médecine, Université de Montréal, Montréal, H3T 1J4, Canada
| | - Stéphane Roy
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal, Québec, H3T 1J4, Canada .,Department of Stomatology, Faculty of Dentistry, Université de Montréal, Montréal, Québec, H3T 1J4, Canada
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37
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Qu F, Palte IC, Gontarz PM, Zhang B, Guilak F. Transcriptomic analysis of bone and fibrous tissue morphogenesis during digit tip regeneration in the adult mouse. FASEB J 2020; 34:9740-9754. [PMID: 32506623 DOI: 10.1096/fj.202000330r] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 04/29/2020] [Accepted: 05/15/2020] [Indexed: 12/31/2022]
Abstract
Humans have limited regenerative potential of musculoskeletal tissues following limb or digit loss. The murine digit has been used to study mammalian regeneration, where stem/progenitor cells (the "blastema") completely regenerate the digit tip after distal, but not proximal, amputation. However, the molecular mechanisms responsible for this response remain to be determined. Here, we evaluated the spatiotemporal formation of bone and fibrous tissues after level-dependent amputation of the murine terminal phalanx and quantified the transcriptome of the repair tissue. Distal (regenerative) and proximal (non-regenerative) amputations showed significant differences in temporal gene expression and tissue regrowth over time. Genes that direct skeletal system development and limb morphogenesis are transiently upregulated during blastema formation and differentiation, including distal Hox genes. Overall, our results suggest that digit tip regeneration is controlled by a gene regulatory network that recapitulates aspects of limb development, and that failure to activate this developmental program results in fibrotic wound healing.
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Affiliation(s)
- Feini Qu
- Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA.,Center of Regenerative Medicine, Washington University, St. Louis, MO, USA.,Shriners Hospitals for Children-St. Louis, St. Louis, MO, USA
| | - Ilan C Palte
- Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA.,Center of Regenerative Medicine, Washington University, St. Louis, MO, USA.,Shriners Hospitals for Children-St. Louis, St. Louis, MO, USA
| | - Paul M Gontarz
- Center of Regenerative Medicine, Washington University, St. Louis, MO, USA
| | - Bo Zhang
- Center of Regenerative Medicine, Washington University, St. Louis, MO, USA
| | - Farshid Guilak
- Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA.,Center of Regenerative Medicine, Washington University, St. Louis, MO, USA.,Shriners Hospitals for Children-St. Louis, St. Louis, MO, USA
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38
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Bothe V, Mahlow K, Fröbisch NB. A histological study of normal and pathological limb regeneration in the Mexican axolotl Ambystoma mexicanum. JOURNAL OF EXPERIMENTAL ZOOLOGY PART B-MOLECULAR AND DEVELOPMENTAL EVOLUTION 2020; 336:116-128. [PMID: 32394624 DOI: 10.1002/jez.b.22950] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 03/30/2020] [Accepted: 04/08/2020] [Indexed: 01/13/2023]
Abstract
Salamanders show unparalleled capacities of tissue regeneration amongst tetrapods (four-legged vertebrates), being able to repair and renew lost or damage body parts, such as tails, jaws, and limbs in a seemingly perfect fashion. Despite countless studies on axolotl (Ambystoma mexicanum) regeneration, only a few studies have thus far compared gross morphological and histological features of the original and regenerated limb skeleton. Therein, most studies have focused on nerves or muscles, while even fewer have provided detailed information about bones and cartilage. This study compares skeletal tissue structures of original and regenerated limbs with respect to tissue level histology. Histological serial sections of 55 axolotl larvae were generated, including 29 limbs that were severed by conspecifics, and 26 that were subject to targeted amputations. Amputations were executed in several larval stages (48, 52, and 53) and at different limb positions (humeral midshaft, above the mesopod). In addition, 3D reconstructions were prepared based on X-ray microtomography scans. The results demonstrate that regenerated forelimbs show a diversity of limb and digit abnormalities as a result of imperfect regeneration. Furthermore, abnormalities were more severe and more frequent in regenerated forelimbs caused by natural bites as compared with regenerated forelimbs after amputation. The results indicate that abnormalities occur frequently after regeneration in larval axolotls contradicting the notion of regeneration generally resulting in perfect limbs.
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Affiliation(s)
- Vivien Bothe
- Museum für Naturkunde, Leibniz Institute for Evolution and Biodiversity Science, Berlin, Germany
| | - Kristin Mahlow
- Museum für Naturkunde, Leibniz Institute for Evolution and Biodiversity Science, Berlin, Germany
| | - Nadia B Fröbisch
- Museum für Naturkunde, Leibniz Institute for Evolution and Biodiversity Science, Berlin, Germany.,Humboldt-Universität zu Berlin, Berlin, Germany
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39
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Zhang W, Das P, Kelangi S, Bei M. Potassium channels as potential drug targets for limb wound repair and regeneration. PRECISION CLINICAL MEDICINE 2020; 3:22-33. [PMID: 32257531 PMCID: PMC7093894 DOI: 10.1093/pcmedi/pbz029] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 12/22/2019] [Indexed: 12/02/2022] Open
Abstract
Background Ion channels are a large family of transmembrane proteins, accessible by soluble membrane-impermeable molecules, and thus are targets for development of therapeutic drugs. Ion channels are the second most common target for existing drugs, after G protein-coupled receptors, and are expected to make a big impact on precision medicine in many different diseases including wound repair and regeneration. Research has shown that endogenous bioelectric signaling mediated by ion channels is critical in non-mammalian limb regeneration. However, the role of ion channels in regeneration of limbs in mammalian systems is not yet defined. Methods To explore the role of potassium channels in limb wound repair and regeneration, the hindlimbs of mouse embryos were amputated at E12.5 when the wound is expected to regenerate and E15.5 when the wound is not expected to regenerate, and gene expression of potassium channels was studied. Results Most of the potassium channels were downregulated, except for the potassium channel kcnj8 (Kir6.1) which was upregulated in E12.5 embryos after amputation. Conclusion This study provides a new mouse limb regeneration model and demonstrates that potassium channels are potential drug targets for limb wound healing and regeneration.
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Affiliation(s)
- Wengeng Zhang
- Center for Engineering in Medicine, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02114, USA.,Shriners Hospital for Children, Boston, MA 02114, USA
| | - Pragnya Das
- Center for Regenerative Developmental Biology, The Forsyth Institute, Cambridge, MA 02116, USA
| | - Sarah Kelangi
- Center for Engineering in Medicine, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02114, USA.,Shriners Hospital for Children, Boston, MA 02114, USA
| | - Marianna Bei
- Center for Engineering in Medicine, Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02114, USA.,Shriners Hospital for Children, Boston, MA 02114, USA
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40
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Kaji DA, Tan Z, Johnson GL, Huang W, Vasquez K, Lehoczky JA, Levi B, Cheah KS, Huang AH. Cellular Plasticity in Musculoskeletal Development, Regeneration, and Disease. J Orthop Res 2020; 38:708-718. [PMID: 31721278 PMCID: PMC7213644 DOI: 10.1002/jor.24523] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 11/04/2019] [Indexed: 02/04/2023]
Abstract
In this review, we highlight themes from a recent workshop focused on "Plasticity of Cell Fate in Musculoskeletal Tissues" held at the Orthopaedic Research Society's 2019 annual meeting. Experts in the field provided examples of mesenchymal cell plasticity during normal musculoskeletal development, regeneration, and disease. A thorough understanding of the biology underpinning mesenchymal cell plasticity may offer a roadmap for promoting regeneration while attenuating pathologic differentiation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:708-718, 2020.
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Affiliation(s)
- Deepak A. Kaji
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, NYC, NY, USA
| | - Zhijia Tan
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong
| | - Gemma L. Johnson
- Department of Orthopedic Surgery, Brigham and Women’s Hospital, Boston, MA, USA,Department of Systems Biology, Harvard Medical School, Boston, MA, USA
| | - Wesley Huang
- Department of Plastic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Kaetlin Vasquez
- Department of Plastic Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Jessica A. Lehoczky
- Department of Orthopedic Surgery, Brigham and Women’s Hospital, Boston, MA, USA
| | - Benjamin Levi
- Department of Plastic Surgery, University of Michigan, Ann Arbor, MI, USA
| | | | - Alice H. Huang
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, NYC, NY, USA
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41
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Muneoka K, Dawson LA. Evolution of epimorphosis in mammals. JOURNAL OF EXPERIMENTAL ZOOLOGY PART B-MOLECULAR AND DEVELOPMENTAL EVOLUTION 2020; 336:165-179. [PMID: 31951104 DOI: 10.1002/jez.b.22925] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 10/29/2019] [Accepted: 12/23/2019] [Indexed: 12/30/2022]
Abstract
Mammalian epimorphic regeneration is rare and digit tip regeneration in mice is the best-studied model for a multi-tissue regenerative event that involves blastema formation. Digit tip regeneration parallels human fingertip regeneration, thus understanding the details of this response can provide insight into developing strategies to expand the potential of human regeneration. Following amputation, the digit stump undergoes a strong histolytic response involving osteoclast-mediated bone degradation that is spatially and temporally linked to the expansion of blastema osteoprogenitor cells. Blastemal differentiation occurs via direct intramembranous ossification. Although robust, digit regeneration is imperfect: The amputated cortical bone is replaced with woven bone and there is excessive bone regeneration restricted to the dorsal-ventral axis. Ontogenetic and phylogenetic analysis of digit regeneration in amphibians and mammals raise the possibility that mammalian blastema is a product of convergent evolution and we hypothesize that digit tip regeneration evolved from a nonregenerative precondition. A model is proposed in which the mammalian blastema evolved in part from an adaptation of two bone repair strategies (the bone remodeling cycle and fracture healing) both of which are conserved across tetrapod vertebrates. The view that epimorphic regeneration evolved in mammals from a nonregenerative precondition is supported by recent studies demonstrating that complex regenerative responses can be induced from a number of different nonregenerative amputation wounds by specific modification of the healing response.
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Affiliation(s)
- Ken Muneoka
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas
| | - Lindsay A Dawson
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas
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Storer MA, Mahmud N, Karamboulas K, Borrett MJ, Yuzwa SA, Gont A, Androschuk A, Sefton MV, Kaplan DR, Miller FD. Acquisition of a Unique Mesenchymal Precursor-like Blastema State Underlies Successful Adult Mammalian Digit Tip Regeneration. Dev Cell 2020; 52:509-524.e9. [PMID: 31902657 DOI: 10.1016/j.devcel.2019.12.004] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 11/11/2019] [Accepted: 12/09/2019] [Indexed: 12/11/2022]
Abstract
Here, we investigate the origin and nature of blastema cells that regenerate the adult murine digit tip. We show that Pdgfra-expressing mesenchymal cells in uninjured digits establish the regenerative blastema and are essential for regeneration. Single-cell profiling shows that the mesenchymal blastema cells are distinct from both uninjured digit and embryonic limb or digit Pdgfra-positive cells. This unique blastema state is environmentally determined; dermal fibroblasts transplanted into the regenerative, but not non-regenerative, digit express blastema-state genes and contribute to bone regeneration. Moreover, lineage tracing with single-cell profiling indicates that endogenous osteoblasts or osteocytes acquire a blastema mesenchymal transcriptional state and contribute to both dermis and bone regeneration. Thus, mammalian digit tip regeneration occurs via a distinct adult mechanism where the regenerative environment promotes acquisition of a blastema state that enables cells from tissues such as bone to contribute to the regeneration of other mesenchymal tissues such as the dermis.
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Affiliation(s)
- Mekayla A Storer
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto M5G 1L7, Canada
| | - Neemat Mahmud
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto M5G 1A8, Canada
| | - Konstantina Karamboulas
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto M5G 1L7, Canada
| | - Michael J Borrett
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto M5G 1L7, Canada; Institute of Medical Sciences, University of Toronto, Toronto M5G 1A8, Canada
| | - Scott A Yuzwa
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto M5G 1L7, Canada
| | - Alexander Gont
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto M5G 1L7, Canada
| | - Alaura Androschuk
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto M5G 1A8, Canada
| | - Michael V Sefton
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto M5G 1A8, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto M5G 1A8, Canada
| | - David R Kaplan
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto M5G 1A8, Canada; Institute of Medical Sciences, University of Toronto, Toronto M5G 1A8, Canada
| | - Freda D Miller
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto M5G 1A8, Canada; Department of Physiology, University of Toronto, Toronto M5G 1A8, Canada; Institute of Medical Sciences, University of Toronto, Toronto M5G 1A8, Canada.
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Mehta AS, Singh A. Insights into regeneration tool box: An animal model approach. Dev Biol 2019; 453:111-129. [PMID: 30986388 PMCID: PMC6684456 DOI: 10.1016/j.ydbio.2019.04.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 04/04/2019] [Accepted: 04/09/2019] [Indexed: 12/20/2022]
Abstract
For ages, regeneration has intrigued countless biologists, clinicians, and biomedical engineers. In recent years, significant progress made in identification and characterization of a regeneration tool kit has helped the scientific community to understand the mechanism(s) involved in regeneration across animal kingdom. These mechanistic insights revealed that evolutionarily conserved pathways like Wnt, Notch, Hedgehog, BMP, and JAK/STAT are involved in regeneration. Furthermore, advancement in high throughput screening approaches like transcriptomic analysis followed by proteomic validations have discovered many novel genes, and regeneration specific enhancers that are specific to highly regenerative species like Hydra, Planaria, Newts, and Zebrafish. Since genetic machinery is highly conserved across the animal kingdom, it is possible to engineer these genes and regeneration specific enhancers in species with limited regeneration properties like Drosophila, and mammals. Since these models are highly versatile and genetically tractable, cross-species comparative studies can generate mechanistic insights in regeneration for animals with long gestation periods e.g. Newts. In addition, it will allow extrapolation of regenerative capabilities from highly regenerative species to animals with low regeneration potential, e.g. mammals. In future, these studies, along with advancement in tissue engineering applications, can have strong implications in the field of regenerative medicine and stem cell biology.
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Affiliation(s)
- Abijeet S Mehta
- Department of Biology, University of Dayton, Dayton, OH, 45469, USA
| | - Amit Singh
- Department of Biology, University of Dayton, Dayton, OH, 45469, USA; Premedical Program, University of Dayton, Dayton, OH, 45469, USA; Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, Dayton, OH, 45469, USA; The Integrative Science and Engineering Center, University of Dayton, Dayton, OH, 45469, USA; Center for Genomic Advocacy (TCGA), Indiana State University, Terre Haute, IN, USA.
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Bone growth as the main determinant of mouse digit tip regeneration after amputation. Sci Rep 2019; 9:9720. [PMID: 31273239 PMCID: PMC6609708 DOI: 10.1038/s41598-019-45521-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 05/08/2019] [Indexed: 01/08/2023] Open
Abstract
Regeneration is classically demonstrated in mammals using mice digit tip. In this study, we compared different amputation plans and show that distally amputated digits regrow with morphology close to normal but fail to regrow the fat pad. Proximally amputated digits do not regrow the phalangeal bone, but the remaining structures (nail, skin and connective tissue), all with intrinsic regenerative capacity, re-establishing integrity indistinguishably in distally and proximally amputated digits. Thus, we suggest that the bone growth promoted by signals and progenitor cells not removed by distal amputations is responsible for the re-establishment of a drastically different final morphology after distal or proximal digit tip amputations. Despite challenging the use of mouse digit tip as a model system for limb regeneration in mammals, these findings evidence a main role of bone growth in digit tip regeneration and suggest that mechanisms that promote joint structures formation should be the main goal of regenerative medicine for limb and digit regrowth.
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45
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Digit Tip Injuries: Current Treatment and Future Regenerative Paradigms. Stem Cells Int 2019; 2019:9619080. [PMID: 30805012 PMCID: PMC6360566 DOI: 10.1155/2019/9619080] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Revised: 12/07/2018] [Accepted: 12/27/2018] [Indexed: 11/18/2022] Open
Abstract
Over the past several decades there has been a profound increase in the understanding of tissue regeneration, driven largely by the observance of the tremendous regenerative capacity in lower order life forms, such as hydra and urodeles. However, it is known that humans and other mammals retain the ability to regenerate the distal phalanges of the digits after amputation. Despite the increased knowledge base on model organisms regarding regenerative paradigms, there is a lack of application of regenerative medicine techniques in clinical practice in regard to digit tip injury. Here, we review the current understanding of digit tip regeneration and discuss gaps that remain in translating regenerative medicine into clinical treatment of digit amputation.
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46
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Cox BD, De Simone A, Tornini VA, Singh SP, Di Talia S, Poss KD. In Toto Imaging of Dynamic Osteoblast Behaviors in Regenerating Skeletal Bone. Curr Biol 2018; 28:3937-3947.e4. [PMID: 30503623 DOI: 10.1016/j.cub.2018.10.052] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 09/19/2018] [Accepted: 10/24/2018] [Indexed: 12/16/2022]
Abstract
Osteoblasts are matrix-depositing cells that can divide and heal bone injuries. Their deep-tissue location and the slow progression of bone regeneration challenge attempts to capture osteoblast behaviors in live tissue at high spatiotemporal resolution. Here, we have developed an imaging platform to monitor and quantify individual and collective behaviors of osteoblasts in adult zebrafish scales, skeletal body armor discs that regenerate rapidly after loss. Using a panel of transgenic lines that visualize and manipulate osteoblasts, we find that a founder pool of osteoblasts emerges through de novo differentiation within one day of scale plucking. These osteoblasts undergo division events that are largely uniform in frequency and orientation to establish a primordium. Osteoblast proliferation dynamics diversify across the primordium by two days after injury, with cell divisions focused near, and with orientations parallel to, the scale periphery, occurring coincident with dynamic localization of fgf20a gene expression. In posterior scale regions, cell elongation events initiate in areas soon occupied by mineralized grooves called radii, beginning approximately 2 days post injury, with patterned osteoblast death events accompanying maturation of these radii. By imaging at single-cell resolution, we detail acquisition of spatiotemporally distinct cell division, motility, and death dynamics within a founder osteoblast pool as bone regenerates.
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Affiliation(s)
- Ben D Cox
- Department of Cell Biology, Regeneration Next, Duke University Medical Center, Durham, NC 27710, USA
| | - Alessandro De Simone
- Department of Cell Biology, Regeneration Next, Duke University Medical Center, Durham, NC 27710, USA
| | - Valerie A Tornini
- Department of Cell Biology, Regeneration Next, Duke University Medical Center, Durham, NC 27710, USA
| | - Sumeet P Singh
- Department of Cell Biology, Regeneration Next, Duke University Medical Center, Durham, NC 27710, USA
| | - Stefano Di Talia
- Department of Cell Biology, Regeneration Next, Duke University Medical Center, Durham, NC 27710, USA.
| | - Kenneth D Poss
- Department of Cell Biology, Regeneration Next, Duke University Medical Center, Durham, NC 27710, USA.
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47
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Dolan CP, Yan M, Zimmel K, Yang TJ, Leininger E, Dawson LA, Muneoka K. Axonal regrowth is impaired during digit tip regeneration in mice. Dev Biol 2018; 445:237-244. [PMID: 30458171 DOI: 10.1016/j.ydbio.2018.11.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 11/12/2018] [Accepted: 11/15/2018] [Indexed: 12/16/2022]
Abstract
Mice are intrinsically capable of regenerating the tips of their digits after amputation. Mouse digit tip regeneration is reported to be a peripheral nerve-dependent event. However, it is presently unknown what types of nerves and Schwann cells innervate the digit tip, and to what extent these cells regenerate in association with the regenerative response. Given the necessity of peripheral nerves for mammalian regeneration, we investigated the neuroanatomy of the unamputated, regenerating, and regenerated mouse digit tip. Using immunohistochemistry for β-III-tubulin (β3T) or neurofilament H (NFH), substance P (SP), tyrosine hydroxylase (TH), myelin protein zero (P0), and glial fibrillary acidic protein (GFAP), we identified peripheral nerve axons (sensory and sympathetic), and myelinating- and non-myelinating-Schwann cells. Our findings show that the digit tip is innervated by two digital nerves that each bifurcate into a bone marrow (BM) and connective tissue (CT) branch. The BM branches are composed of sympathetic axons that are ensheathed by non-myelinating-Schwann cells whereas the CT branches are composed of sensory and sympathetic axons and are ensheathed by myelinating- and non-myelinating-Schwann cells. The regenerated digit neuroanatomy differs from unamputated digit in several key ways. First, there is 7.5 fold decrease in CT branch axons in the regenerated digit compared to the unampuated digit. Second, there is a 5.6 fold decrease in myelinating-Schwann cells in the regenerated digit compared to the unamputated digit that is consistent with the decrease in CT branch axons. Importantly, we also find that the central portion of the regenerating digit blastema is aneural, with axons and Schwann cells restricted to peripheral and distal blastema regions. Finally, we show that even with impaired innervation, digits maintain the ability to regenerate after re-amputation. Taken together, these data indicate that nerve regeneration is impaired in the context of mouse digit tip regeneration.
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Affiliation(s)
- Connor P Dolan
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.
| | - Mingquan Yan
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.
| | - Katherine Zimmel
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.
| | - Tae-Jung Yang
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.
| | - Eric Leininger
- Department of Cell and Molecular Biology, School of Science and Engineering, Tulane University, New Orleans, LA 70118, USA.
| | - Lindsay A Dawson
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.
| | - Ken Muneoka
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA; Department of Cell and Molecular Biology, School of Science and Engineering, Tulane University, New Orleans, LA 70118, USA.
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48
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Hughes MW, Jiang TX, Plikus MV, Guerrero-Juarez CF, Lin CH, Schafer C, Maxson R, Widelitz RB, Chuong CM. Msx2 Supports Epidermal Competency during Wound-Induced Hair Follicle Neogenesis. J Invest Dermatol 2018; 138:2041-2050. [PMID: 29577917 PMCID: PMC6109435 DOI: 10.1016/j.jid.2018.02.043] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 02/06/2018] [Accepted: 02/10/2018] [Indexed: 12/11/2022]
Abstract
Cutaneous wounds in adult mammals typically heal by scarring. However, large full-thickness wounds undergo wound-induced hair follicle neogenesis (WIHN), a form of regeneration. Here, we show that WIHN requires transient expression of epidermal Msx2 in two phases: the wound margin early and the wound center late. Msx2 expression is present in the migrating epithelium during early wound healing and then presents in the epithelium and mesenchyme later in the wound center. WIHN is abrogated in germline and epithelial-specific Msx2 mutant mice. Unlike the full-length Msx2 promoter, a minimal Msx2 promoter fails activation in the wound center, suggesting complex regulation of Msx2 expression. The Msx2 promoter binding sites include Tcf/Lef, Jun/Creb, Pax3, and three SMAD sites. However, basal epithelial-induced BMP suppression by noggin overexpression did not affect WIHN. We propose that Msx2 signaling is required for the epidermis to acquire spatiotemporal competence during WIHN. Topologically, hair regeneration dominates in the wound center, coinciding with late Msx2 expression. Together, these results suggest that intrinsic Msx2 expression supports epithelial competency during hair follicle neogenesis. This work provides insight into endogenous mechanisms modulating competency of adult epidermal progenitors for mammalian ectodermal appendage neogenesis, and offers the target Msx2 for future regeneration-promoting therapies.
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Affiliation(s)
- Michael W Hughes
- Department of Pathology, School of Medicine, University of Southern California, Los Angeles, California, USA; International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan; Institute of Clinical Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Ting-Xin Jiang
- Department of Pathology, School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Maksim V Plikus
- Department of Developmental and Cell Biology, School of Biological Sciences, University of California Irvine, Irvine, California, USA; Stem Cell Research Center, Center for Complex Biological Systems, University of California Irvine, Irvine, California, USA
| | - Christian Fernando Guerrero-Juarez
- Department of Developmental and Cell Biology, School of Biological Sciences, University of California Irvine, Irvine, California, USA; Stem Cell Research Center, Center for Complex Biological Systems, University of California Irvine, Irvine, California, USA
| | - Chien-Hong Lin
- International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan; Department of Basic Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan
| | - Christopher Schafer
- Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Robert Maxson
- Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Randall B Widelitz
- Department of Pathology, School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Cheng-Ming Chuong
- Department of Pathology, School of Medicine, University of Southern California, Los Angeles, California, USA; International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan; Institute of Clinical Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; Department of Basic Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan; Integrative Stem Cell Center, China Medical University Hospital, China Medical University, 2 Yude Road, North District, Taichung, Taiwan.
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49
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Zhang M, Chen Y, Xu H, Yang L, Yuan F, Li L, Xu Y, Chen Y, Zhang C, Lin G. Melanocortin Receptor 4 Signaling Regulates Vertebrate Limb Regeneration. Dev Cell 2018; 46:397-409.e5. [PMID: 30130530 PMCID: PMC6107305 DOI: 10.1016/j.devcel.2018.07.021] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 05/28/2018] [Accepted: 07/21/2018] [Indexed: 11/16/2022]
Abstract
Melanocortin 4 receptor (Mc4r) plays a crucial role in the central control of energy homeostasis, but its role in peripheral organs has not been fully explored. We have investigated the roles of hypothalamus-mediated energy metabolism during Xenopus limb regeneration. We report that hypothalamus injury inhibits Xenopus tadpole limb regeneration. By loss-of-function and gain-of-function studies, we show that Mc4r signaling is required for limb regeneration in regeneration-competent tadpoles and stimulates limb regeneration in later-stage regeneration-defective tadpoles. It regulates limb regeneration through modulating energy homeostasis and ROS production. Even more interestingly, our results demonstrate that Mc4r signaling is regulated by innervation and α-MSH substitutes for the effect of nerves in limb regeneration. Mc4r signaling is also required for mouse digit regeneration. Thus, our findings link vertebrate limb regeneration with Mc4r-mediated energy homeostasis and provide a new avenue for understanding Mc4r signaling in the peripheral organs.
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Affiliation(s)
- Mengshi Zhang
- Research Center for Translational Medicine, Translational Medical Center for Stem Cell Therapy, and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China
| | - Youwei Chen
- Research Center for Translational Medicine, Translational Medical Center for Stem Cell Therapy, and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China
| | - Hanqian Xu
- Research Center for Translational Medicine, Translational Medical Center for Stem Cell Therapy, and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China; Stem Cell Institute, Department of Genetics Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA
| | - Li Yang
- Research Center for Translational Medicine, Translational Medical Center for Stem Cell Therapy, and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China
| | - Feng Yuan
- Research Center for Translational Medicine, Translational Medical Center for Stem Cell Therapy, and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China
| | - Lei Li
- Research Center for Translational Medicine, Translational Medical Center for Stem Cell Therapy, and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China
| | - Ying Xu
- Research Center for Translational Medicine, Translational Medical Center for Stem Cell Therapy, and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China
| | - Ying Chen
- Stem Cell Institute, Department of Genetics Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.
| | - Chao Zhang
- Research Center for Translational Medicine, Translational Medical Center for Stem Cell Therapy, and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China.
| | - Gufa Lin
- Research Center for Translational Medicine, Translational Medical Center for Stem Cell Therapy, and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China; Stem Cell Institute, Department of Genetics Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.
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50
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Taghiyar L, Hosseini S, Safari F, Bagheri F, Fani N, Stoddart MJ, Alini M, Eslaminejad MB. New insight into functional limb regeneration: A to Z approaches. J Tissue Eng Regen Med 2018; 12:1925-1943. [PMID: 30011424 DOI: 10.1002/term.2727] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2017] [Revised: 02/19/2018] [Accepted: 07/06/2018] [Indexed: 12/31/2022]
Abstract
Limb/digit amputation is a common event in humans caused by trauma, medical illness, or surgery. Although the loss of a digit is not lethal, it affects quality of life and imposes high costs on amputees. In recent years, the increasing interest in limb regeneration has led to enhanced scientific knowledge. However, the limited ability to develop functional limb regeneration in the clinical setting suggests that a challenging issue remains in limb regeneration. Recently, the emergence of regenerative engineering is a promising field to address this challenge and close the gap between science and clinical applications. Cell signalling and molecular mechanisms involved in the limb regeneration process have been extensively studied; however, there is still insufficient data on cell therapy and tissue engineering for limb regeneration. In this review, we intend to focus on therapeutic approaches for limb regeneration that are closely related to gene, immune, and stem cell therapies, as well as tissue engineering approaches that take into consideration the peculiar developmental properties of the limbs. In addition, we attempt to identify the challenges of these strategies for limb regeneration studies in terms of clinical settings and as a road map to accomplish the goal of functional human limb regeneration.
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Affiliation(s)
- Leila Taghiyar
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Department of Developmental Biology, University of Science and Culture, Tehran, Iran
| | - Samaneh Hosseini
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Fatemeh Safari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Fatemeh Bagheri
- Department of Biotechnology, Faculty of Chemical Engineering, Tarbiat Modares University, Tehran, Iran
| | - Nesa Fani
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | | | - Mauro Alini
- AO Research Institute Davos, Davos, Switzerland
| | - Mohamadreza Baghaban Eslaminejad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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