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Allouh MZ, Rizvi SFA, Alamri A, Jimoh Y, Aouda S, Ouda ZH, Hamad MIK, Perez-Cruet M, Chaudhry GR. Mesenchymal stromal/stem cells from perinatal sources: biological facts, molecular biomarkers, and therapeutic promises. Stem Cell Res Ther 2025; 16:127. [PMID: 40055783 PMCID: PMC11889844 DOI: 10.1186/s13287-025-04254-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 02/25/2025] [Indexed: 05/13/2025] Open
Abstract
The use of mesenchymal stem cells (MSCs) from perinatal tissue sources has gained attention due to their availability and lack of significant ethical or moral concerns. These cells have a higher proliferative capability than adult MSCs and less immunogenic or tumorigenesis risk than fetal and embryonic stem cells. Additionally, they do not require invasive isolation methods like fetal and adult MSCs. We reviewed the main biological and therapeutic aspects of perinatal MSCs in a three-part article. In the first part, we revised the main biological features and characteristics of MSCs and the advantages of perinatal MSCs over other types of SCs. In the second part, we provided a detailed molecular background for the main biomarkers that can be used to identify MSCs. In the final part, we appraised the therapeutic application of perinatal MSCs in four major degenerative disorders: degenerative disc disease, retinal degenerative diseases, ischemic heart disease, and neurodegenerative diseases. In conclusion, there is no single specific molecular marker to identify MSCs. We recommend using at least two positive markers of stemness (CD29, CD73, CD90, or CD105) and two negative markers (CD34, CD45, or CD14) to exclude the hematopoietic origin. Moreover, utilizing perinatal MSCs for managing degenerative diseases presents a promising therapeutic approach. This review emphasizes the significance of employing more specialized progenitor cells that originated from the perinatal MSCs. The review provides scientific evidence from the literature that applying these progenitor cells in therapeutic procedures provides a greater regenerative capacity than the original primitive MSCs. Finally, this review provides a valuable reference for researchers exploring perinatal MSCs and their therapeutic applications.
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Affiliation(s)
- Mohammed Z Allouh
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, P. O. Box: 15551, Al Ain, UAE.
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, 48309, USA.
| | - Syed Faizan Ali Rizvi
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, 48309, USA
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
| | - Ali Alamri
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, 48309, USA
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
| | - Yusuf Jimoh
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, 48309, USA
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
| | - Salma Aouda
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, UAE
| | - Zakaria H Ouda
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, P. O. Box: 15551, Al Ain, UAE
| | - Mohammad I K Hamad
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, P. O. Box: 15551, Al Ain, UAE
| | - Mick Perez-Cruet
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, 48309, USA
- Department of Neurosurgery, Corewell Health, Royal Oak, MI, USA
| | - G Rasul Chaudhry
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, 48309, USA.
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA.
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Almahasneh F, Abu-El-Rub E, Khasawneh RR, Almazari R. Effects of high glucose and severe hypoxia on the biological behavior of mesenchymal stem cells at various passages. World J Stem Cells 2024; 16:434-443. [PMID: 38690519 PMCID: PMC11056633 DOI: 10.4252/wjsc.v16.i4.434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 02/05/2024] [Accepted: 03/18/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have been extensively studied for therapeutic potential, due to their regenerative and immunomodulatory properties. Serial passage and stress factors may affect the biological characteristics of MSCs, but the details of these effects have not been recognized yet. AIM To investigate the effects of stress factors (high glucose and severe hypoxia) on the biological characteristics of MSCs at different passages, in order to optimize the therapeutic applications of MSCs. METHODS In this study, we investigated the impact of two stress conditions; severe hypoxia and high glucose on human adipose-tissue derived MSCs (hAD-MSCs) at passages 6 (P6), P8, and P10. Proliferation, senescence and apoptosis were evaluated measuring WST-1, senescence-associated beta-galactosidase, and annexin V, respectively. RESULTS Cells at P6 showed decreased proliferation and increased apoptosis under conditions of high glucose and hypoxia compared to control, while the extent of senescence did not change significantly under stress conditions. At P8 hAD-MSCs cultured in stress conditions had a significant decrease in proliferation and apoptosis and a significant increase in senescence compared to counterpart cells at P6. Cells cultured in high glucose at P10 had lower proliferation and higher senescence than their counterparts in the previous passage, while no change in apoptosis was observed. On the other hand, MSCs cultured under hypoxia showed decreased senescence, increased apoptosis and no significant change in proliferation when compared to the same conditions at P8. CONCLUSION These results indicate that stress factors had distinct effects on the biological processes of MSCs at different passages, and suggest that senescence may be a protective mechanism for MSCs to survive under stress conditions at higher passage numbers.
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Affiliation(s)
- Fatimah Almahasneh
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
| | - Ejlal Abu-El-Rub
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan.
| | - Ramada R Khasawneh
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
| | - Rawan Almazari
- Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
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Song YT, Li YQ, Tian MX, Hu JG, Zhang XR, Liu PC, Zhang XZ, Zhang QY, Zhou L, Zhao LM, Li-Ling J, Xie HQ. Application of antibody-conjugated small intestine submucosa to capture urine-derived stem cells for bladder repair in a rabbit model. Bioact Mater 2022; 14:443-455. [PMID: 35415280 PMCID: PMC8978277 DOI: 10.1016/j.bioactmat.2021.11.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 10/26/2021] [Accepted: 11/12/2021] [Indexed: 02/08/2023] Open
Abstract
The need for bladder reconstruction and side effects of cystoplasty have spawned the demand for the development of alternative material substitutes. Biomaterials such as submucosa of small intestine (SIS) have been widely used as patches for bladder repair, but the outcomes are not fully satisfactory. To capture stem cells in situ has been considered as a promising strategy to speed up the process of re-cellularization and functionalization. In this study, we have developed an anti-CD29 antibody-conjugated SIS scaffold (AC-SIS) which is capable of specifically capturing urine-derived stem cells (USCs) in situ for tissue repair and regeneration. The scaffold has exhibited effective capture capacity and sound biocompatibility. In vivo experiment proved that the AC-SIS scaffold could promote rapid endothelium healing and smooth muscle regeneration. The endogenous stem cell capturing scaffolds has thereby provided a new revenue for developing effective and safer bladder patches.
We developed an anti-CD29 antibody-crosslinked submucosa of small intestine scaffold (AC-SIS). AC-SIS is capable of specifically capturing urine-derived stem cells (USCs) as well as possesses a sound biocompatibility. AC-SIS promotes in situ tissue regeneration by facilitating the repair of bladder epithelium, smooth muscle and angiogenesis. Design and application of endogenous stem cell capturing scaffolds provides a new strategy for bladder repair.
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Affiliation(s)
- Yu-Ting Song
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Yan-Qing Li
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Mao-Xuan Tian
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.,Department of Aesthetic Surgery, The People's Hospital of Pengzhou, Chengdu, Sichuan, 611930, China
| | - Jun-Gen Hu
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Xiu-Ru Zhang
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.,Surgery of Spine and Spinal Cord, Henan Provincial People's Hospital, Zhengzhou, Henan, 450000, China
| | - Peng-Cheng Liu
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.,Department of Burn and Plastic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Xiu-Zhen Zhang
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Qing-Yi Zhang
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Li Zhou
- Research Core Facility of West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Long-Mei Zhao
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Jesse Li-Ling
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.,Department of Medical Genetics and Prenatal Diagnosis, West China Second Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Hui-Qi Xie
- Laboratory of Stem Cell and Tissue Engineering, Orthopedic Research Institute, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
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Wright A, Arthaud-Day ML, Weiss ML. Therapeutic Use of Mesenchymal Stromal Cells: The Need for Inclusive Characterization Guidelines to Accommodate All Tissue Sources and Species. Front Cell Dev Biol 2021; 9:632717. [PMID: 33665190 PMCID: PMC7921162 DOI: 10.3389/fcell.2021.632717] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 01/07/2021] [Indexed: 12/12/2022] Open
Abstract
Following their discovery over 50 years ago, mesenchymal stromal cells (MSCs) have become one of the most studied cellular therapeutic products by both academia and industry due to their regenerative potential and immunomodulatory properties. The promise of MSCs as a therapeutic modality has been demonstrated by preclinical data yet has not translated to consistent, successful clinical trial results in humans. Despite the disparities across the field, MSC shareholders are unified under one common goal-to use MSCs as a therapeutic modality to improve the quality of life for those suffering from a malady in which the standard of care is suboptimal or no longer effective. Currently, there is no Food and Drug Administration (FDA)-approved MSC therapy on the market in the United States although several MSC products have been granted regulatory approval in other countries. In this review, we intend to identify hurdles that are impeding therapeutic progress and discuss strategies that may aid in accomplishing this universal goal of widespread therapeutic use.
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Affiliation(s)
- Adrienne Wright
- Department of Anatomy and Physiology, Kansas State University, Manhattan, KS, United States
| | - Marne L Arthaud-Day
- Department of Management, Kansas State University, Manhattan, KS, United States
| | - Mark L Weiss
- Department of Anatomy and Physiology, Kansas State University, Manhattan, KS, United States.,Midwest Institute of Comparative Stem Cell Biotechnology, Kansas State University, Manhattan, KS, United States
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Scutera S, Salvi V, Lorenzi L, Piersigilli G, Lonardi S, Alotto D, Casarin S, Castagnoli C, Dander E, D'Amico G, Sozzani S, Musso T. Adaptive Regulation of Osteopontin Production by Dendritic Cells Through the Bidirectional Interaction With Mesenchymal Stromal Cells. Front Immunol 2018; 9:1207. [PMID: 29910810 PMCID: PMC5992779 DOI: 10.3389/fimmu.2018.01207] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 05/14/2018] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) exert immunosuppressive effects on immune cells including dendritic cells (DCs). However, many details of the bidirectional interaction of MSCs with DCs are still unsolved and information on key molecules by which DCs can modulate MSC functions is limited. Here, we report that osteopontin (OPN), a cytokine involved in homeostatic and pathophysiologic responses, is constitutively expressed by DCs and regulated in the DC/MSC cocultures depending on the activation state of MSCs. Resting MSCs promoted OPN production, whereas the production of OPN was suppressed when MSCs were activated by proinflammatory cytokines (i.e., TNF-α, IL-6, and IL-1β). OPN induction required cell-to-cell contact, mediated at least in part, by β1 integrin (CD29). Conversely, activated MSCs inhibited the release of OPN via the production of soluble factors with a major role played by Prostaglandin E2 (PGE2). Accordingly, pretreatment with indomethacin significantly abrogated the MSC-mediated suppression of OPN while the direct addition of exogenous PGE2 inhibited OPN production by DCs. Furthermore, DC-conditioned medium promoted osteogenic differentiation of MSCs with a concomitant inhibition of adipogenesis. These effects were paralleled by the repression of the adipogenic markers PPARγ, adiponectin, and FABP4, and induction of the osteogenic markers alkaline phosphatase, RUNX2, and of the bone-anabolic chemokine CCL5. Notably, blocking OPN activity with RGD peptides or with an antibody against CD29, one of the OPN receptors, prevented the effects of DC-conditioned medium on MSC differentiation and CCL5 induction. Because MSCs have a key role in maintenance of bone marrow (BM) hematopoietic stem cell niche through reciprocal regulation with immune cells, we investigated the possible MSC/DC interaction in human BM by immunohistochemistry. Although DCs (CD1c+) are a small percentage of BM cells, we demonstrated colocalization of CD271+ MSCs with CD1c+ DCs in normal and myelodysplastic BM. OPN reactivity was observed in occasional CD1c+ cells in the proximity of CD271+ MSCs. Altogether, these results candidate OPN as a signal modulated by MSCs according to their activation status and involved in DC regulation of MSC differentiation.
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Affiliation(s)
- Sara Scutera
- Department of Public Health and Pediatric Sciences, University of Turin, Turin, Italy
| | - Valentina Salvi
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Luisa Lorenzi
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Giorgia Piersigilli
- Department of Public Health and Pediatric Sciences, University of Turin, Turin, Italy
| | - Silvia Lonardi
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Daniela Alotto
- Skin Bank, Department of General and Specialized Surgery, A.O.U. Citta della Salute e della Scienza di Torino, Turin, Italy
| | - Stefania Casarin
- Skin Bank, Department of General and Specialized Surgery, A.O.U. Citta della Salute e della Scienza di Torino, Turin, Italy
| | - Carlotta Castagnoli
- Skin Bank, Department of General and Specialized Surgery, A.O.U. Citta della Salute e della Scienza di Torino, Turin, Italy
| | - Erica Dander
- "M. Tettamanti" Research Center, Pediatric Department, University of Milano-Bicocca, Monza, Italy
| | - Giovanna D'Amico
- "M. Tettamanti" Research Center, Pediatric Department, University of Milano-Bicocca, Monza, Italy
| | - Silvano Sozzani
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Tiziana Musso
- Department of Public Health and Pediatric Sciences, University of Turin, Turin, Italy
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Zhang Y, Pan X, Shi Z, Cai H, Gao Y, Zhang W. Sustained release of stem cell factor in a double network hydrogel for ex vivo culture of cord blood-derived CD34 + cells. Cell Prolif 2018; 51:e12407. [PMID: 29143396 PMCID: PMC6528907 DOI: 10.1111/cpr.12407] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Accepted: 10/13/2017] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVES Stem cell factor (SCF) is considered as a commonly indispensable cytokine for proliferation of haematopoietic stem cells (HSCs), which is used in large dosages during ex vivo culture. The work presented here aimed to reduce the consumption of SCF by sustained release but still support cells proliferation and maintain the multipotency of HSCs. MATERIALS AND METHODS Stem cell factor was physically encapsulated within a hyaluronic acid/gelatin double network (HGDN) hydrogel to achieve a slow release rate. CD34+ cells were cultured within the SCF-loaded HGDN hydrogel for 14 days. The cell number, phenotype and functional capacity were investigated after culture. RESULTS The HGDN hydrogels had desirable properties and encapsulated SCF kept being released for more than 6 days. SCF remained the native bioactivity, and the proliferation of HSCs within the SCF-loaded HGDN hydrogel was not affected, although the consumption of SCF was only a quarter in comparison with the conventional culture. Moreover, CD34+ cells harvested from the SCF-loaded HGDN hydrogels generated more multipotent colony-forming units (CFU-GEMM). CONCLUSION The data suggested that the SCF-loaded HGDN hydrogel could support ex vivo culture of HSCs, thus providing a cost-effective culture protocol for HSCs.
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Affiliation(s)
- Yuanhao Zhang
- State Key Laboratory of Bioreactor EngineeringShanghai Key Laboratory of Functional Materials ChemistryEast China University of Science and TechnologyShanghai200237China
| | - Xiuwei Pan
- State Key Laboratory of Bioreactor EngineeringShanghai Key Laboratory of Functional Materials ChemistryEast China University of Science and TechnologyShanghai200237China
| | - Zhen Shi
- State Key Laboratory of Bioreactor EngineeringShanghai Key Laboratory of Functional Materials ChemistryEast China University of Science and TechnologyShanghai200237China
| | - Haibo Cai
- State Key Laboratory of Bioreactor EngineeringShanghai Key Laboratory of Functional Materials ChemistryEast China University of Science and TechnologyShanghai200237China
| | - Yun Gao
- State Key Laboratory of Bioreactor EngineeringShanghai Key Laboratory of Functional Materials ChemistryEast China University of Science and TechnologyShanghai200237China
| | - Weian Zhang
- State Key Laboratory of Bioreactor EngineeringShanghai Key Laboratory of Functional Materials ChemistryEast China University of Science and TechnologyShanghai200237China
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