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Arriola-Alvarez I, Jaunarena I, Izeta A, Lafuente H. Progenitor Cell Sources for 3D Bioprinting of Lymphatic Vessels and Potential Clinical Application. Tissue Eng Part A 2024; 30:353-366. [PMID: 37950710 DOI: 10.1089/ten.tea.2023.0204] [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] [Indexed: 11/13/2023] Open
Abstract
The lymphatic system maintains tissue fluid homeostasis and it is involved in the transport of nutrients and immunosurveillance. It also plays a pivotal role in both pathological and regenerative processes. Lymphatic development in the embryo occurs by polarization and proliferation of lymphatic endothelial cells from the lymph sacs, that is, lymphangiogenesis. Alternatively, lymphvasculogenesis further contributes to the formation of lymphatic vessels. In adult tissues, lymphatic formation rarely occurs under physiological conditions, being restricted to pathological processes. In lymphvasculogenesis, progenitor cells seem to be a source of lymphatic vessels. Indeed, mesenchymal stem cells, adipose stem cells, endothelial progenitor cells, and colony-forming endothelial cells are able to promote lymphatic regeneration by different mechanisms, such as direct differentiation and paracrine effects. In this review, we summarize what is known on the diverse stem/progenitor cell niches available for the lymphatic system, emphasizing the potential that these cells hold for lymphatic tissue engineering through 3D bioprinting and their translation to clinical application.
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Affiliation(s)
- Inazio Arriola-Alvarez
- Tissue Engineering Group, Biogipuzkoa Health Research Institute, Donostia-San Sebastián, Spain
| | - Ibon Jaunarena
- Gynecology Oncology Unit, Donostia University Hospital, Donostia-San Sebastián, Spain
- Obstetrics and Gynaecology Group, Biogipuzkoa Health Research Institute, Donostia-San Sebastián, Spain
- University of the Basque Country (UPV/EHU), Department of Medical Surgical Specialties, Leioa, Spain
| | - Ander Izeta
- Tissue Engineering Group, Biogipuzkoa Health Research Institute, Donostia-San Sebastián, Spain
- Department of Biomedical Engineering and Sciences, Tecnun-University of Navarra, Donostia-San Sebastián, Spain
| | - Héctor Lafuente
- Tissue Engineering Group, Biogipuzkoa Health Research Institute, Donostia-San Sebastián, Spain
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2
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Suarez AC, Hammel JH, Munson JM. Modeling lymphangiogenesis: Pairing in vitro and in vivo metrics. Microcirculation 2023; 30:e12802. [PMID: 36760223 PMCID: PMC10121924 DOI: 10.1111/micc.12802] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 01/20/2023] [Accepted: 02/07/2023] [Indexed: 02/11/2023]
Abstract
Lymphangiogenesis is the mechanism by which the lymphatic system develops and expands new vessels facilitating fluid drainage and immune cell trafficking. Models to study lymphangiogenesis are necessary for a better understanding of the underlying mechanisms and to identify or test new therapeutic agents that target lymphangiogenesis. Across the lymphatic literature, multiple models have been developed to study lymphangiogenesis in vitro and in vivo. In vitro, lymphangiogenesis can be modeled with varying complexity, from monolayers to hydrogels to explants, with common metrics for characterizing proliferation, migration, and sprouting of lymphatic endothelial cells (LECs) and vessels. In comparison, in vivo models of lymphangiogenesis often use genetically modified zebrafish and mice, with in situ mouse models in the ear, cornea, hind leg, and tail. In vivo metrics, such as activation of LECs, number of new lymphatic vessels, and sprouting, mirror those most used in vitro, with the addition of lymphatic vessel hyperplasia and drainage. The impacts of lymphangiogenesis vary by context of tissue and pathology. Therapeutic targeting of lymphangiogenesis can have paradoxical effects depending on the pathology including lymphedema, cancer, organ transplant, and inflammation. In this review, we describe and compare lymphangiogenic outcomes and metrics between in vitro and in vivo studies, specifically reviewing only those publications in which both testing formats are used. We find that in vitro studies correlate well with in vivo in wound healing and development, but not in the reproductive tract or the complex tumor microenvironment. Considerations for improving in vitro models are to increase complexity with perfusable microfluidic devices, co-cultures with tissue-specific support cells, the inclusion of fluid flow, and pairing in vitro models of differing complexities. We believe that these changes would strengthen the correlation between in vitro and in vivo outcomes, giving more insight into lymphangiogenesis in healthy and pathological states.
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Affiliation(s)
- Aileen C. Suarez
- Fralin Biomedical Research Institute, Virginia Tech, Roanoke, VA
- Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences, Department of Biomedical Engineering & Mechanics, Virginia Tech, Blacksburg, VA
| | - Jennifer H. Hammel
- Fralin Biomedical Research Institute, Virginia Tech, Roanoke, VA
- Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences, Department of Biomedical Engineering & Mechanics, Virginia Tech, Blacksburg, VA
| | - Jennifer M. Munson
- Fralin Biomedical Research Institute, Virginia Tech, Roanoke, VA
- Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences, Department of Biomedical Engineering & Mechanics, Virginia Tech, Blacksburg, VA
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3
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Lymphatic Tissue Bioengineering for the Treatment of Postsurgical Lymphedema. BIOENGINEERING (BASEL, SWITZERLAND) 2022; 9:bioengineering9040162. [PMID: 35447722 PMCID: PMC9025804 DOI: 10.3390/bioengineering9040162] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 03/17/2022] [Accepted: 03/20/2022] [Indexed: 01/28/2023]
Abstract
Lymphedema is characterized by progressive and chronic tissue swelling and inflammation from local accumulation of interstitial fluid due to lymphatic injury or dysfunction. It is a debilitating condition that significantly impacts a patient's quality of life, and has limited treatment options. With better understanding of the molecular mechanisms and pathophysiology of lymphedema and advances in tissue engineering technologies, lymphatic tissue bioengineering and regeneration have emerged as a potential therapeutic option for postsurgical lymphedema. Various strategies involving stem cells, lymphangiogenic factors, bioengineered matrices and mechanical stimuli allow more precisely controlled regeneration of lymphatic tissue at the site of lymphedema without subjecting patients to complications or iatrogenic injuries associated with surgeries. This review provides an overview of current innovative approaches of lymphatic tissue bioengineering that represent a promising treatment option for postsurgical lymphedema.
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Abstract
PURPOSE OF REVIEW Lymphatic vessels are found in most tissues, with the exception of the cornea and the central nervous system. Tissues that have high exposure to antigens, such as the skin and the intestine, have especially extensive lymphatic vascular networks. Despite being densely vascularized with blood vessels, adipose tissue is poorly permeated with lymphatic vasculature. Here, we focus on the recent advances in the research on adipose tissue lymphatics and present a lymphatic-focused analysis of published single-cell and single-nucleus RNA sequencing datasets of adipose tissues. RECENT FINDINGS Although lymphatic expansion in obesity may limit inflammation and promote glycerol efflux from adipose tissue, lymphatic endothelial cells (LECs) secrete factors that reduce brown adipocyte thermogenesis. Transcriptomic analyses of these cells show that they express common lymphatic markers such as Prox1, but datasets from different studies show great variation in gene expression values due to the low number of captured LECs, depot differences, and species-specific gene expression patterns. SUMMARY As the importance of LECs in the homeostasis of adipose tissue has become evident, investigators want to shed light on the specific interactions of lymphatics with other cell types in adipose tissues. Extracting LECs from readily available transcriptomics datasets provides a standpoint for investigators for future research. However, systematic studies are needed to reveal unique identities according to depot and species-specific LEC signatures.
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Abstract
Adipose tissue, once thought to be an inert receptacle for energy storage, is now recognized as a complex tissue with multiple resident cell populations that actively collaborate in response to diverse local and systemic metabolic, thermal, and inflammatory signals. A key participant in adipose tissue homeostasis that has only recently captured broad scientific attention is the lymphatic vasculature. The lymphatic system's role in lipid trafficking and mediating inflammation makes it a natural partner in regulating adipose tissue, and evidence supporting a bidirectional relationship between lymphatics and adipose tissue has accumulated in recent years. Obesity is now understood to impair lymphatic function, whereas altered lymphatic function results in aberrant adipose tissue deposition, though the molecular mechanisms governing these phenomena have yet to be fully elucidated. We will review our current understanding of the relationship between adipose tissue and the lymphatic system here, focusing on known mechanisms of lymphatic-adipose crosstalk.
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Affiliation(s)
- Gregory P Westcott
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
- Joslin Diabetes Center, Boston, MA 02215, USA
- Harvard Medical School, Boston, MA 02215, USA
| | - Evan D Rosen
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
- Harvard Medical School, Boston, MA 02215, USA
- Broad Institute, Cambridge, MA 02142, USA
- Correspondence: Evan D. Rosen, MD, PhD, Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.
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Use of adipose-derived stem cells in lymphatic tissue engineering and regeneration. Arch Plast Surg 2021; 48:559-567. [PMID: 34583446 PMCID: PMC8490113 DOI: 10.5999/aps.2021.00339] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 06/16/2021] [Indexed: 12/11/2022] Open
Abstract
The potential to differentiate into different cell lines, added to the easy and cost-effective method of extraction, makes adipose-derived stem cells (ADSCs) an object of interest in lymphedema treatment. Our study’s goal was to conduct a comprehensive systematic review of the use of ADSCs in lymphatic tissue engineering and regeneration. On July 23, 2019, using PubMed/MEDLINE, Cochrane Clinical Answers, Cochrane Central Register of Controlled Trials, and Embase databases, we conducted a systematic review of published literature on the use of ADSCs in lymphatic tissue engineering and regeneration. There were no language or time frame limitations, and the following search strategy was applied: ((Adipose stem cell) OR Adipose-derived stem cell)) AND ((Lymphedema) OR Breast Cancer Lymphedema). Only original research manuscripts were included. Fourteen studies fulfilled the inclusion criteria. Eleven studies were experimental (in vitro or in vivo in animals), and only three were clinical. Publications on the topic demonstrated that ADSCs promote lymphangiogenesis, and its effect could be enhanced by modulation of vascular endothelial growth factor-C, interleukin-7, prospero homeobox protein 1, and transforming growth factor-β1. Pilot clinical studies included 11 patients with breast cancer-related lymphedema, and no significant side effects were present at 12-month follow-up. Literature on the use of ADSCs in lymphatic tissue engineering and regeneration demonstrated promising data. Clinical evidence is still in its infancy, but the scientific community agrees that ADSCs can be useful in regenerative lymphangiogenesis. Data collected in this review indicate that unprecedented advances in lymphedema treatment can be anticipated in the upcoming years.
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Kruglikov IL, Joffin N, Scherer PE. The MMP14-caveolin axis and its potential relevance for lipoedema. Nat Rev Endocrinol 2020; 16:669-674. [PMID: 32792644 DOI: 10.1038/s41574-020-0395-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/10/2020] [Indexed: 12/15/2022]
Abstract
Lipoedema is associated with widespread adipose tissue expansion, particularly in the proximal extremities. The mechanisms that drive the development of lipoedema are unclear. In this Perspective article, we propose a new model for the pathophysiology of lipoedema. We suggest that lipoedema is an oestrogen-dependent disorder of adipose tissue, which is triggered by a dysfunction of caveolin 1 (CAV1) and subsequent uncoupling of feedback mechanisms between CAV1, the matrix metalloproteinase MMP14 and oestrogen receptors. In addition, reduced CAV1 activity also leads to the activation of ERα and impaired regulation of the lymphatic system through the transcription factor prospero homeobox 1 (PROX1). The resulting upregulation of these factors could effectively explain the main known features of lipoedema, such as adipose hypertrophy, dysfunction of blood and lymphatic vessels, the overall oestrogen dependence and the associated sexual dimorphism, and the mechanical compliance of adipose tissue.
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Affiliation(s)
| | - Nolwenn Joffin
- Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Philipp E Scherer
- Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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Chen K, Sinelnikov MY, Reshetov IV, Timashev P, Gu Y, Mu L, Lu P, Zhang Y. Therapeutic Potential of Mesenchymal Stem Cells for Postmastectomy Lymphedema: A Literature Review. Clin Transl Sci 2020; 14:54-61. [PMID: 33460321 PMCID: PMC7877822 DOI: 10.1111/cts.12864] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 07/15/2020] [Indexed: 12/14/2022] Open
Abstract
Upper limb lymphedema is one of the most common complications after breast cancer surgery and radiotherapy. Despite various physical therapy and surgical options available, the impaired lymph fluid drainage may be progressive due to lymphatic vascular insufficiency making treatment more difficulty. Stem cell therapy provides a promising alternative in the treatment of various chronic diseases. The wide applicability of cell therapy has been reviewed throughout literature. This review provides an overview of recent progress in the therapeutic effect of adult stem cells for primary and secondary lymphedema after breast surgery in preclinical studies and clinical cases. We start with a brief introduction about the pathophysiological mechanisms of postmastectomy lymphedema. Regarding existing treatments, we systematically summarize the benefits and limitations of recent progress. Because of their multidirectional differentiation potential and growth factor secretion, stem cell therapy shows promising results in the management of light to severe lymphedema. Increasing evidences have demonstrated a noticeable reduction in postmastectomy lymphedema and increased lymph-angiogenesis after specific stem cell therapy. Current data suggests that stem cell therapy in lymphedema treatment provides reversal of pathological reorganization associated with lymphedema progression. Finally, we propose potential strategies for overcoming the challenges in the development of multipotent progenitor cells for the treatment and prevention of lymphedema in clinical practice.
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Affiliation(s)
- Kuo Chen
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia
| | - Mikhail Y Sinelnikov
- Institute for Regenerative Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Igor V Reshetov
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia
| | - Petr Timashev
- Institute for Regenerative Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Yuanting Gu
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lan Mu
- Peking University People's Hospital, Beijing, China
| | - Pengwei Lu
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuanyuan Zhang
- Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, North Carolina, USA
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Ricci M, Amato B, Barati S, Compagna R, Veselenyiova D, Kenanoglu S, Stuppia L, Beccari T, Baglivo M, Kurti D, Krajcovic J, Serrani R, Dundar M, Basha SH, Chiurazzi P, Bertelli M. Two rare PROX1 variants in patients with lymphedema. Mol Genet Genomic Med 2020; 8:e1424. [PMID: 32757260 PMCID: PMC7549596 DOI: 10.1002/mgg3.1424] [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: 04/22/2020] [Revised: 06/08/2020] [Accepted: 07/02/2020] [Indexed: 12/11/2022] Open
Abstract
Background The PROX1 gene is specifically expressed in a subpopulation of endothelial cells that, by budding and sprouting, give rise to the lymphatic system. It also plays a critical role in neurogenesis and during development of many organs, such as the eye lens, liver, and pancreas. Methods We used next‐generation sequencing (NGS) to sequence the DNA of a cohort of 246 Italian patients with lymphatic malformations. We first investigated 29 known disease‐causing genes: 235 of 246 patients tested negative and were then retested for a group of candidate genes, including PROX1, selected from a database of mouse models. The aim of the study was to define these patients’ genotypes and explore the role of the candidate gene PROX1 in lymphedema. Results Two of 235 probands were found to carry rare heterozygous missense variants in PROX1. In silico analysis of these variants—p.(Leu590His) and p.(Gly106Asp)—indicates that the overall protein structure was altered by changes in interactions between nearby residues, leading to functional protein defects. Conclusions Our results suggest that PROX1 is a new candidate gene for predisposition to lymphedema.
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Affiliation(s)
- Maurizio Ricci
- Division of Rehabilitation Medicine, Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Ancona, Italy
| | - Bruno Amato
- Department of Clinical Medicine and Surgery, University Federico II of Naples, Naples, Italy
| | | | - Rita Compagna
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Dominika Veselenyiova
- MAGI Euregio, Bolzano, Italy.,Department of Biology, Faculty of Natural Sciences, University of Ss. Cyril and Methodius In Trnava, Trnava, Slovakia
| | - Sercan Kenanoglu
- MAGI Euregio, Bolzano, Italy.,Department of Medical Genetics, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Liborio Stuppia
- Aging and Translational Medicine Research Center (CeSI-MeT), University "G. d'Annunzio", Chieti-Pescara, Italy
| | - Tommaso Beccari
- Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
| | | | - Danjela Kurti
- MAGI Euregio, Bolzano, Italy.,MAGI-Balkan, Tirana, Albania
| | - Juraj Krajcovic
- Department of Biology, Faculty of Natural Sciences, University of Ss. Cyril and Methodius In Trnava, Trnava, Slovakia
| | - Roberta Serrani
- Division of Rehabilitation Medicine, Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Ancona, Italy
| | - Munis Dundar
- Department of Medical Genetics, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Syed H Basha
- Innovative Informatica Technologies, Telangana, India
| | - Pietro Chiurazzi
- Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore, Rome, Italy.,Fondazione Policlinico Universitario "A.Gemelli" IRCCS, UOC Genetica Medica, Rome, Italy
| | - Matteo Bertelli
- MAGI Euregio, Bolzano, Italy.,EBTNA-Lab, Rovereto, TN, Italy.,MAGI's Lab, Rovereto, TN, Italy
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10
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Hu LR, Pan J. Adipose-derived stem cell therapy shows promising results for secondary lymphedema. World J Stem Cells 2020; 12:612-620. [PMID: 32843917 PMCID: PMC7415246 DOI: 10.4252/wjsc.v12.i7.612] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 03/29/2020] [Accepted: 06/02/2020] [Indexed: 02/06/2023] Open
Abstract
Lymphedema is mainly identified by progressive soft tissue swelling in impaired lymphatic system. Secondary lymphedema attributed to cancer therapy, parasite infection, and trauma remains a serious global disease. Patients with lymphedema suffer swelling, pain, and fatigue, with the dysfunction of the deformed extremities reducing the quality of life and increasing the risk of infection and lymphangiosarcoma. Adipose-derived stem cells (ADSCs) possess prominent regenerative potential to differentiate into multilineage cells, and produce various lymphangiogenic factors, making ADSC therapy a promising approach for lymphedema. The development of lymphedema consists of local inflammation, the fibrosis of lymphatic vessels, and the deposition of adipose fat. Existing animal models do not mimic the chronic inflammation environment, therefore suitable models are required in further studies. Some signal pathways and molecular mechanisms in physiological and pathological lymphagiogenesis remain unclear. In previous animal and human trials, ADSC therapy reduced edema in varying degrees. A larger number of trials with larger samples and longer follow-up periods are required to verify the efficiency and feasibility of ADSC therapy. ADSCs are of easy availability and immune exemption, making them a candidate for lymphedema treatment. Whether ADSCs enhance malignant characteristics or trigger the malignant change deserves further exploration and study before ADSC therapy can be made widely available.
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Affiliation(s)
- Li-Ru Hu
- State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jian Pan
- Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
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11
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Li ZJ, Yang E, Li YZ, Liang ZY, Huang JZ, Yu NZ, Long X. Application and prospect of adipose stem cell transplantation in treating lymphedema. World J Stem Cells 2020; 12:676-687. [PMID: 32843921 PMCID: PMC7415250 DOI: 10.4252/wjsc.v12.i7.676] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 05/08/2020] [Accepted: 05/28/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Lymphedema is a chronic, debilitating and incurable disease that affects 0.13%-2% of the global population. Emerging evidence indicates that adipose-derived stem cells (ADSCs) might serve as suitable seed cells for lymphatic tissue engineering and lymphedema therapy. AIM To summarize applications of ADSCs for treating lymphedema in both animal studies and clinical trials. METHODS A systematic search was performed on four databases - PubMed, Clinicaltrials.gov, the evidence-based Cochrane Library, and OVID - using the following search string: ("lymphedema" or "lymphoedema" or "lymphangiogenesis") and ("adipose-derived stem cells" or "adipose-derived stromal cells" or "adipose-derived regenerative cells"). A manual search was performed by skimming the references of relevant studies. Animal studies and clinical trials using adipose-derived cells for the treatment of any kind of lymphedema were included. RESULTS A total of eight research articles published before November 2019 were included for this analysis. Five articles focused on animal studies and another three focused on clinical trials. ADSC transplantation therapy was demonstrated to be effective against lymphedema in all studies. The animal studies found that coadministration of ADSCs and controlled-release vascular endothelial growth factor-C or platelet-rich plasma could improve the effectiveness of ADSC therapy. Three sequential clinical trials were conducted on breast cancer-related lymphedema patients, and all showed favorable results. CONCLUSION ADSC-based therapy is a promising option for treating lymphedema. Large-scale, multicenter randomized controlled trials are needed to develop more effective and durable therapeutic strategies.
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Affiliation(s)
- Zhu-Jun Li
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Elan Yang
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yun-Zhu Li
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Zheng-Yun Liang
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Jiu-Zuo Huang
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Nan-Ze Yu
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Xiao Long
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
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12
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Kamat P, Frueh FS, McLuckie M, Sanchez-Macedo N, Wolint P, Lindenblatt N, Plock JA, Calcagni M, Buschmann J. Adipose tissue and the vascularization of biomaterials: Stem cells, microvascular fragments and nanofat-a review. Cytotherapy 2020; 22:400-411. [PMID: 32507607 DOI: 10.1016/j.jcyt.2020.03.433] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 02/27/2020] [Accepted: 03/12/2020] [Indexed: 12/13/2022]
Abstract
Tissue defects in the human body after trauma and injury require precise reconstruction to regain function. Hence, there is a great demand for clinically translatable approaches with materials that are both biocompatible and biodegradable. They should also be able to adequately integrate within the tissue through sufficient vascularization. Adipose tissue is abundant and easily accessible. It is a valuable tissue source in regenerative medicine and tissue engineering, especially with regard to its angiogenic potential. Derivatives of adipose tissue, such as microfat, nanofat, microvascular fragments, stromal vascular fraction and stem cells, are commonly used in research, but also clinically to enhance the vascularization of implants and grafts at defect sites. In plastic surgery, adipose tissue is harvested via liposuction and can be manipulated in three ways (macro-, micro- and nanofat) in the operating room, depending on its ultimate use. Whereas macro- and microfat are used as a filling material for soft tissue injuries, nanofat is an injectable viscous extract that primarily induces tissue remodeling because it is rich in growth factors and stem cells. In contrast to microfat that adds volume to a defect site, nanofat has the potential to be easily combined with scaffold materials due to its liquid and homogenous consistency and is particularly attractive for blood vessel formation. The same is true for microvascular fragments that are easily isolated from adipose tissue through collagenase digestion. In preclinical animal models, it has been convincingly shown that these vascular fragments inosculate with host vessels and subsequently accelerate scaffold perfusion and host tissue integration. Adipose tissue is also an ideal source of stem cells. It yields larger quantities of cells than any other source and is easier to access for both the patient and doctor compared with other sources such as bone marrow. They are often used for tissue regeneration in combination with biomaterials. Adipose-derived stem cells can be applied unmodified or as single cell suspensions. However, certain pretreatments, such as cultivation under hypoxic conditions or three-dimensional spheroids production, may provide substantial benefit with regard to subsequent vascularization in vivo due to induced growth factor production. In this narrative review, derivatives of adipose tissue and the vascularization of biomaterials are addressed in a comprehensive approach, including several sizes of derivatives, such as whole fat flaps for soft tissue engineering, nanofat or stem cells, their secretome and exosomes. Taken together, it can be concluded that adipose tissue and its fractions down to the molecular level promote, enhance and support vascularization of biomaterials. Therefore, there is a high potential of the individual fat component to be used in regenerative medicine.
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Affiliation(s)
- Pranitha Kamat
- Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Zurich, Switzerland; Department of Plastic Surgery and Hand Surgery, University of Zurich, Zurich, Switzerland
| | - Florian S Frueh
- Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Zurich, Switzerland
| | - Michelle McLuckie
- Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Zurich, Switzerland
| | - Nadia Sanchez-Macedo
- Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Zurich, Switzerland
| | - Petra Wolint
- Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Zurich, Switzerland
| | - Nicole Lindenblatt
- Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Zurich, Switzerland
| | - Jan A Plock
- Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Zurich, Switzerland; Department of Plastic Surgery and Hand Surgery, University of Zurich, Zurich, Switzerland
| | - Maurizio Calcagni
- Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Zurich, Switzerland
| | - Johanna Buschmann
- Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, Zurich, Switzerland.
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13
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Tian YI, Zhang X, Torrejon K, Danias J, Gindina S, Nayyar A, Du Y, Xie Y. A bioengineering approach to Schlemm's canal-like stem cell differentiation for in vitro glaucoma drug screening. Acta Biomater 2020; 105:203-213. [PMID: 31982588 DOI: 10.1016/j.actbio.2020.01.033] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 01/20/2020] [Accepted: 01/21/2020] [Indexed: 12/30/2022]
Abstract
Human Schlemm's canal (HSC) cells are critical for understanding outflow physiology and glaucoma etiology. However, primary donor cells frequently used in research are difficult to isolate. HSC cells exhibit both vascular and lymphatic markers. Human adipose-derived stem cells (ADSCs) represent a potential source of HSC due to their capacity to differentiate into both vascular and lymphatic endothelial cells, via VEGF-A and VEGF-C. Shear stress plays a critical role in maintaining HSC integrity, function, and PROX1 expression. Additionally, the human trabecular meshwork (HTM) microenvironment could provide cues for HSC-like differentiation. We hypothesize that subjecting ADSCs to VEGF-A or VEGF-C, shear stress, and co-culture with HTM cells could provide biological, mechanical, and cellular cues necessary for HSC-like differentiation. To test this hypothesis, effects of VEGF-A, VEGF-C, and shear stress on ADSC differentiation were examined and compared to primary HSC cells in terms of cell morphology, and HSC marker expression using qPCR, immunoblotting, and immunocytochemistry analysis. Furthermore, the effect of co-culture with HTM cells on porous scaffolds on ADSC differentiation was studied. Treatment with VEGF-C under shear stress is effective in differentiating ADSCs into PROX1-expressing HSC-like cells. Co-culture with HTM cells on porous scaffolds leads to HTM/ADSC-derived HSC-like constructs that regulate through-flow and respond as expected to dexamethasone. STATEMENT OF SIGNIFICANCE: We successfully generated human Schlemm's canal (HSC) like cells from adipocyte-derived stem cells induced by biochemical and biomechanical cues as well as bioengineered human trabecular meshwork (HTM) on micropatterned, porous SU8 scaffolds. These stem cell-derived HSC-like cells co-cultured with HTM cells on SU8 scaffolds can regulate through-flow, and in particular, are responsive to steroid treatment as expected. These findings show that ADSC-derived HSC-like cells have the potential to recreate the ocular outflow pathway for in vitro glaucoma drug screening. To the best of our knowledge, it is the very first time to demonstrate derivation of Schlemm's canal-like cells from stem cells. It provides an important alternative source to primary Schlemm's canal cells that are very difficult to be isolated and cultured from human donors.
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Affiliation(s)
- Yangzi Isabel Tian
- College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, 257 Fuller Road, Albany, NY 12203, USA
| | - Xulang Zhang
- College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, 257 Fuller Road, Albany, NY 12203, USA
| | - Karen Torrejon
- Glauconix Biosciences, Inc., 251 Fuller Road, Albany, NY 12203, USA
| | - John Danias
- SUNY Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY 11203, USA
| | - Sofya Gindina
- SUNY Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY 11203, USA
| | - Ashima Nayyar
- SUNY Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY 11203, USA
| | - Yiqin Du
- University of Pittsburg School of Medicine, 203 Lothrop Street, Pittsburgh, PA 15213, USA
| | - Yubing Xie
- College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, 257 Fuller Road, Albany, NY 12203, USA.
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Forte AJ, Boczar D, Huayllani MT, McLaughlin SA, Bagaria S. Use of Gene Transfer Vectors in Lymphedema Treatment: A Systematic Review. Cureus 2019; 11:e5887. [PMID: 31772857 PMCID: PMC6837272 DOI: 10.7759/cureus.5887] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Different delivery mechanisms have been proposed in the literature for targeted therapies in the treatment of lymphedema. They vary from simple and direct injection to sophisticated induction of gene expression in a targeted tissue. We conducted a systematic review of publications assessing the use of viral vectors for gene transfer in lymphedema treatment. We hypothesized that viral vectors are an effective way to deliver targeted therapy in lymphedema treatment. We conducted a comprehensive systematic review of the published literature on targeted therapies associated with lymphedema surgery using the PubMed database. Eligibility criteria excluded papers that reported use of viral vectors for other medical conditions. Abstracts, presentations, reviews, meta-analyses, and non-English language articles were also excluded. From 21 potential articles found in the literature, fourteen fulfilled study eligibility criteria. Positive outcomes in terms of lymphangiogenesis were seen. The viral vectors used included adenovirus and recombinant adeno-associated virus. Most of the genes expressed were growth factors, but expression of dominant-negative transforming growth factor-β1 receptor-II or Prox1 was also proposed. Five studies targeted genetic expression on lymphedema tissue, five on transplanted lymph nodes, two on skeletal muscle, and one on adipose-derived stem cells. Publications assessing use of viral vectors for gene transfer in lymphedema treatment demonstrated that it is an effective mechanism of delivering targeted therapies. However, to date, all studies were experimental and further studies must be performed before translating these therapies into clinical practice.
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Affiliation(s)
- Antonio J Forte
- Plastic Surgery, Mayo Clinic Florida - Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Jacksonville, USA
| | - Daniel Boczar
- Plastic Surgery, Mayo Clinic Florida - Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Jacksonville, USA
| | - Maria T Huayllani
- Plastic Surgery, Mayo Clinic Florida - Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Jacksonville, USA
| | - Sarah A McLaughlin
- Surgery, Mayo Clinic Florida - Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Jacksonville, USA
| | - Sanjay Bagaria
- Surgery, Mayo Clinic Florida - Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Jacksonville, USA
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15
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Sun Y, Lu B, Deng J, Jiang Z, Cao W, Dai T, Li S. IL-7 enhances the differentiation of adipose-derived stem cells toward lymphatic endothelial cells through AKT signaling. Cell Biol Int 2019; 43:394-401. [PMID: 30690788 DOI: 10.1002/cbin.11093] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 12/21/2018] [Indexed: 12/12/2022]
Abstract
Our study was designed to investigate the effects of IL-7 during the differentiation process of adipose-derived stem cells (ADSCs) toward lymphatic endothelial cells (LECs). IL-7 was added to the traditional induced medium, which was called the IL-7 (+) group, while the group that used traditional induced medium was called the IL-7 (-) group. After 7 days of induction of ADSCs, a comprehensive analysis was conducted between these two groups. We examined the changes in Prox1, LYVE-1, Podoplanin and VEGFR-3 on the RNA and protein level and found that the expression of LEC markers in the IL-7 (+) group was higher than in the IL-7 (-) group. The characteristics of differentiated cells were confirmed by flow cytometry and immunofluorescence. At the same time, we detected the MAPK/ERK and PI3K/AKT pathway involved in the differentiation process, and we found that the phosphorylation of AKT increased, however the expression of ERK was not significantly changed. In conclusion, our study found that IL-7 could improve the differentiation efficiency of ADSCs toward LECs through AKT signaling pathways.
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Affiliation(s)
- Yiyu Sun
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China
| | - Bolun Lu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China
| | - Jingcheng Deng
- Department of Plastic and Reconstructive Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P. R. China
| | - Zhaohua Jiang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China
| | - Weigang Cao
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China
| | - Tingting Dai
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China
| | - Shengli Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, P. R. China
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Blei F. Update March 2017. Lymphat Res Biol 2017. [DOI: 10.1089/lrb.2017.29019.fb] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
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