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Trapana J, Weinerman J, Lee D, Sedani A, Constantinescu D, Best TM, Hornicek FJ, Hare JM. Cell-based therapy in the treatment of musculoskeletal diseases. Stem Cells Transl Med 2024; 13:959-978. [PMID: 39226104 PMCID: PMC11465182 DOI: 10.1093/stcltm/szae049] [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: 03/13/2023] [Accepted: 05/21/2024] [Indexed: 09/04/2024] Open
Abstract
A limited number of tissues can spontaneously regenerate following injury, and even fewer can regenerate to a state comparable to mature, healthy adult tissue. Mesenchymal stem cells (MSCs) were first described in the 1960s-1970s by Friedenstein et al as a small population of bone marrow cells with osteogenic potential and abilities to differentiate into chondrocytes. In 1991, Arnold Caplan coined the term "mesenchymal cells" after identifying these cells as a theoretical precursor to bone, cartilage, tendon, ligament, marrow stroma, adipocyte, dermis, muscle, and connective tissues. MSCs are derived from periosteum, fat, and muscle. Another attractive property of MSCs is their immunoregulatory and regenerative properties, which result from crosstalk with their microenvironment and components of the innate immune system. Collectively, these properties make MSCs potentially attractive for various therapeutic purposes. MSCs offer potential in sports medicine, aiding in muscle recovery, meniscal tears, and tendon and ligament injuries. In joint disease, MSCs have the potential for chondrogenesis and reversing the effects of osteoarthritis. MSCs have also demonstrated potential application to the treatment of degenerative disc disease of the cervical, thoracic, and lumbar spine.
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Affiliation(s)
- Justin Trapana
- Department of Orthopaedics, University of Miami Miller School of Medicine, Miami, United States
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, United States
| | - Jonathan Weinerman
- Department of Orthopaedics, University of Miami Miller School of Medicine, Miami, United States
| | - Danny Lee
- Department of Orthopaedics, University of Miami Miller School of Medicine, Miami, United States
| | - Anil Sedani
- Department of Orthopaedics, University of Miami Miller School of Medicine, Miami, United States
| | - David Constantinescu
- Department of Orthopaedics, University of Miami Miller School of Medicine, Miami, United States
| | - Thomas M Best
- Department of Orthopaedics, University of Miami Miller School of Medicine, Miami, United States
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, United States
| | - Francis J Hornicek
- Department of Orthopaedics, University of Miami Miller School of Medicine, Miami, United States
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, United States
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, United States
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Ju R, Gao X, Zhang C, Tang W, Tian W, He M. Exogenous MSC based tissue regeneration: a review of immuno-protection strategies from biomaterial scaffolds. J Mater Chem B 2024; 12:8868-8882. [PMID: 39171946 DOI: 10.1039/d4tb00778f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Abstract
Mesenchymal stem cell (MSC)-based tissue engineering holds great potential for regenerative medicine as a means of replacing damaged or lost tissues to restore their structure and function. However, the efficacy of MSC-based regeneration is frequently limited by the low survival rate and limited survival time of transplanted MSCs. Despite the inherent immune privileges of MSCs, such as low expression of major histocompatibility complex antigens, tolerogenic properties, local immunosuppressive microenvironment creation, and induction of immune tolerance, immune rejection remains a major obstacle to their survival and regenerative potential. Evidence suggests that immune protection strategies can enhance MSC therapeutic efficacy by prolonging their survival and maintaining their biological functions. Among various immune protection strategies, biomaterial-based scaffolds or cell encapsulation systems that mediate the interaction between transplanted MSCs and the host immune system or spatially isolate MSCs from the immune system for a specific time period have shown great promise. In this review, we provide a comprehensive overview of these biomaterial-based immune protection strategies employed for exogenous MSCs, highlighting the crucial role of modulating the immune microenvironment. Each strategy is critically examined, discussing its strengths, limitations, and potential applications in MSC-based tissue engineering. By elucidating the mechanisms behind immune rejection and exploring immune protection strategies, we aim to address the challenges faced by MSC-based tissue engineering and pave the way for enhancing the therapeutic outcomes of MSC therapies. The insights gained from this review will contribute to the development of more effective strategies to protect transplanted MSCs from immune rejection and enable their successful application in regenerative medicine.
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Affiliation(s)
- Rongbai Ju
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xinhui Gao
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Chi Zhang
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Wei Tang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Weidong Tian
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Min He
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
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Singh A, Midha V, Kochhar GS, Shen B, Sood A. Management of Perianal Fistulizing Crohn's Disease. Inflamm Bowel Dis 2024; 30:1579-1603. [PMID: 37672347 DOI: 10.1093/ibd/izad195] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Indexed: 09/08/2023]
Abstract
Perianal fistulizing Crohn's disease (CD) represents a severe phenotype of CD that is associated with significant morbidity and reduction in quality of life. Perianal fistulizing CD is caused by a complex interplay of genetic predisposition, immune dysregulation, gut dysbiosis, and various unknown physiological and mechanical factors. A multidisciplinary approach is hence required for optimal management . A detailed anatomical description and classification of perianal fistula, including comprehensive clinical, endoscopic, and radiological diagnostic workup, is an important prerequisite to treatment. For simple perianal fistulas, use of antibiotics and immunomodulators, with or without fistulotomy, are appropriate measures. The medical management of complex perianal fistula, on the other hand, requires adequate control of infection before initiation of therapy with immunomodulators. In active complex perianal fistula, anti-tumor necrosis factors remain the most accepted therapy, with concomitant use of antibiotics or immunomodulators enhancing the efficacy. For patients refractory to anti-tumor necrosis factors, treatment with anti-integrins, anti-interleukins, and small molecules is being evaluated. Mesenchymal stem cells, hyperbaric oxygen therapy, and exclusive enteral nutrition have also been investigated as adjunct therapies. Despite the expansion of the medical armamentarium, a large proportion of the patients require surgical interventions. In this review, we provide an up-to-date overview of the pathophysiology, clinical presentation, diagnosis, and medical management of perianal fistulizing CD. A brief overview of the surgical management of perianal fistulizing CD is also provided.
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Affiliation(s)
- Arshdeep Singh
- Department of Gastroenterology, Dayanand Medical College, Ludhiana, India
| | - Vandana Midha
- Department of Internal Medicine, Dayanand Medical College, Ludhiana, India
| | - Gursimran Singh Kochhar
- Division of Gastroenterology, Hepatology and Nutrition, Allegheny Health Network, Pittsburgh, PA, USA
| | - Bo Shen
- Center for Interventional Inflammatory Bowel Disease, NewYork-Presbyterian Hospital, Columbia University Irving Medical Center, New York, NY, USA
| | - Ajit Sood
- Department of Gastroenterology, Dayanand Medical College, Ludhiana, India
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Gregersen E, Kresse JC, Atay JCL, Boysen AT, Nejsum P, Eijken M, Nørregaard R. Comparative study of systemic and local delivery of mesenchymal stromal cells for the treatment of chronic kidney disease. Front Cell Dev Biol 2024; 12:1456416. [PMID: 39234562 PMCID: PMC11373351 DOI: 10.3389/fcell.2024.1456416] [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: 06/28/2024] [Accepted: 08/02/2024] [Indexed: 09/06/2024] Open
Abstract
Renal fibrosis, characterized by excessive extracellular matrix accumulation, leads to a progressive decline of renal function and is a common endpoint of chronic kidney disease (CKD). Current treatments primarily focus on managing underlying diseases, offering limited direct intervention for the fibrotic process. This study explores the anti-fibrotic potential of human adipose-derived mesenchymal stromal cells (MSCs) and their derived extracellular vesicles (EVs) in the context of CKD, emphasizing the effects of systemic versus local delivery methods. Preconditioned MSCs (Pr-MSCs) were treated with TNF-α and IFN-γ to enhance their immunomodulatory capabilities, and demonstrated significant anti-fibrotic effects in vitro, reducing mRNA expression of fibrosis markers in TGF-β stimulated HKC-8 cells. Our in vivo findings from a murine unilateral ureteral obstruction (UUO) model of CKD showed that local deliveries of Pr-MSCs reduced collagen deposition and increased expression of the anti-inflammatory cytokine IL-10. Systemic administration of Pr-MSCs did not show any significant effect on UUO-induced injury. In addition, EVs did not replicate the anti-fibrotic effects observed with their parent cells, suggesting that soluble proteins or metabolites secreted by Pr-MSCs might be the primary mediators of the anti-fibrotic and immunomodulatory effects. This study provides critical insights into the therapeutic efficacy of MSCs, highlighting the importance of delivery methods and the potential of preconditioning strategies in enhancing MSC-based therapies for renal fibrosis.
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Affiliation(s)
- Emil Gregersen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | | | | | - Anders Toftegaard Boysen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
| | - Peter Nejsum
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
| | - Marco Eijken
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Rikke Nørregaard
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
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Kostecka A, Kalamon N, Skoniecka A, Koczkowska M, Skowron PM, Piotrowski A, Pikuła M. Adipose-derived mesenchymal stromal cells in clinical trials: Insights from single-cell studies. Life Sci 2024; 351:122761. [PMID: 38866216 DOI: 10.1016/j.lfs.2024.122761] [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: 04/02/2024] [Revised: 05/15/2024] [Accepted: 05/27/2024] [Indexed: 06/14/2024]
Abstract
Mesenchymal Stromal Cells (MSCs) offer tremendous potential for the treatment of various diseases and their healing properties have been explored in hundreds of clinical trials. These trails primarily focus on immunological and neurological disorders, as well as regenerative medicine. Adipose tissue is a rich source of mesenchymal stromal cells and methods to obtain and culture adipose-derived MSCs (AD-MSCs) have been well established. Promising results from pre-clinical testing of AD-MSCs activity prompted clinical trials that further led to the approval of AD-MSCs for the treatment of complex perianal fistulas in Crohn's disease and subcutaneous tissue defects. However, AD-MSC heterogeneity along with various manufacturing protocols or different strategies to boost their activity create the need for standardized quality control procedures and safety assessment of the intended cell product. High-resolution transcriptomic methods have been recently gaining attention, as they deliver insight into gene expression profiles of individual cells, helping to deconstruct cellular hierarchy and differentiation trajectories, and to understand cell-cell interactions within tissues. This article presents a comprehensive overview of completed clinical trials evaluating the safety and efficacy of AD-MSC treatment, together with current single-cell studies of human AD-MSC. Furthermore, our work emphasizes the increasing significance of single-cell research in elucidating the mechanisms of cellular action and predicting their therapeutic effects.
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Affiliation(s)
- Anna Kostecka
- Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland; 3P - Medicine Laboratory, Medical University of Gdansk, Gdansk, Poland.
| | - Natalia Kalamon
- Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
| | - Aneta Skoniecka
- Laboratory of Tissue Engineering and Regenerative Medicine, Division of Embryology, Faculty of Medicine, Medical University of Gdansk, Dębinki 1, 80-211 Gdańsk, Poland.
| | - Magdalena Koczkowska
- Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland; 3P - Medicine Laboratory, Medical University of Gdansk, Gdansk, Poland.
| | - Piotr M Skowron
- Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland.
| | - Arkadiusz Piotrowski
- Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland; 3P - Medicine Laboratory, Medical University of Gdansk, Gdansk, Poland.
| | - Michał Pikuła
- Laboratory of Tissue Engineering and Regenerative Medicine, Division of Embryology, Faculty of Medicine, Medical University of Gdansk, Dębinki 1, 80-211 Gdańsk, Poland.
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Pharoun J, Berro J, Sobh J, Abou-Younes MM, Nasr L, Majed A, Khalil A, Joseph, Stephan, Faour WH. Mesenchymal stem cells biological and biotechnological advances: Implications for clinical applications. Eur J Pharmacol 2024; 977:176719. [PMID: 38849038 DOI: 10.1016/j.ejphar.2024.176719] [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: 01/30/2024] [Revised: 05/31/2024] [Accepted: 06/05/2024] [Indexed: 06/09/2024]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are multipotent stem cells that are able to differentiate into multiple lineages including bone, cartilage, muscle and fat. They hold immunomodulatory properties and therapeutic ability to treat multiple diseases, including autoimmune and chronic degenerative diseases. In this article, we reviewed the different biological properties, applications and clinical trials of MSCs. Also, we discussed the basics of manufacturing conditions, quality control, and challenges facing MSCs in the clinical setting. METHODS Extensive review of the literature was conducted through the databases PubMed, Google Scholar, and Cochrane. Papers published since 2015 and covering the clinical applications and research of MSC therapy were considered. Furthermore, older papers were considered when referring to pioneering studies in the field. RESULTS The most widely studied stem cells in cell therapy and tissue repair are bone marrow-derived mesenchymal stem cells. Adipose tissue-derived stem cells became more common and to a lesser extent other stem cell sources e.g., foreskin derived MSCs. MSCs therapy were also studied in the setting of COVID-19 infections, ischemic strokes, autoimmune diseases, tumor development and graft rejection. Multiple obstacles, still face the standardization and optimization of MSC therapy such as the survival and the immunophenotype and the efficiency of transplanted cells. MSCs used in clinical settings displayed heterogeneity in their function despite their extraction from healthy donors and expression of similar surface markers. CONCLUSION Mesenchymal stem cells offer a rising therapeutic promise in various diseases. However, their potential use in clinical applications requires further investigation.
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Affiliation(s)
- Jana Pharoun
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Jana Berro
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Jeanine Sobh
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | | | - Leah Nasr
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Ali Majed
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Alia Khalil
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Joseph
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Stephan
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Wissam H Faour
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36.
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Swain HN, Boyce PD, Bromet BA, Barozinksy K, Hance L, Shields D, Olbricht GR, Semon JA. Mesenchymal stem cells in autoimmune disease: A systematic review and meta-analysis of pre-clinical studies. Biochimie 2024; 223:54-73. [PMID: 38657832 DOI: 10.1016/j.biochi.2024.04.009] [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: 01/30/2024] [Revised: 04/08/2024] [Accepted: 04/20/2024] [Indexed: 04/26/2024]
Abstract
Mesenchymal Stem Cells (MSCs) are of interest in the clinic because of their immunomodulation capabilities, capacity to act upstream of inflammation, and ability to sense metabolic environments. In standard physiologic conditions, they play a role in maintaining the homeostasis of tissues and organs; however, there is evidence that they can contribute to some autoimmune diseases. Gaining a deeper understanding of the factors that transition MSCs from their physiological function to a pathological role in their native environment, and elucidating mechanisms that reduce their therapeutic relevance in regenerative medicine, is essential. We conducted a Systematic Review and Meta-Analysis of human MSCs in preclinical studies of autoimmune disease, evaluating 60 studies that included 845 patient samples and 571 control samples. MSCs from any tissue source were included, and the study was limited to four autoimmune diseases: multiple sclerosis, rheumatoid arthritis, systemic sclerosis, and lupus. We developed a novel Risk of Bias tool to determine study quality for in vitro studies. Using the International Society for Cell & Gene Therapy's criteria to define an MSC, most studies reported no difference in morphology, adhesion, cell surface markers, or differentiation into bone, fat, or cartilage when comparing control and autoimmune MSCs. However, there were reported differences in proliferation. Additionally, 308 biomolecules were differentially expressed, and the abilities to migrate, invade, and form capillaries were decreased. The findings from this study could help to explain the pathogenic mechanisms of autoimmune disease and potentially lead to improved MSC-based therapeutic applications.
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Affiliation(s)
- Hailey N Swain
- Department of Biological Sciences, Missouri University of Science and Technology, USA
| | - Parker D Boyce
- Department of Biological Sciences, Missouri University of Science and Technology, USA
| | - Bradley A Bromet
- Department of Biological Sciences, Missouri University of Science and Technology, USA
| | - Kaiden Barozinksy
- Department of Biological Sciences, Missouri University of Science and Technology, USA
| | - Lacy Hance
- Department of Biological Sciences, Missouri University of Science and Technology, USA
| | - Dakota Shields
- Department of Mathematics and Statistics, Missouri University of Science and Technology, USA
| | - Gayla R Olbricht
- Department of Mathematics and Statistics, Missouri University of Science and Technology, USA
| | - Julie A Semon
- Department of Biological Sciences, Missouri University of Science and Technology, USA.
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Marquez-Curtis LA, Elliott JAW. Mesenchymal stromal cells derived from various tissues: Biological, clinical and cryopreservation aspects: Update from 2015 review. Cryobiology 2024; 115:104856. [PMID: 38340887 DOI: 10.1016/j.cryobiol.2024.104856] [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: 11/28/2023] [Revised: 01/26/2024] [Accepted: 01/30/2024] [Indexed: 02/12/2024]
Abstract
Mesenchymal stromal cells (MSCs) have become one of the most investigated and applied cells for cellular therapy and regenerative medicine. In this update of our review published in 2015, we show that studies continue to abound regarding the characterization of MSCs to distinguish them from other similar cell types, the discovery of new tissue sources of MSCs, and the confirmation of their properties and functions that render them suitable as a therapeutic. Because cryopreservation is widely recognized as the only technology that would enable the on-demand availability of MSCs, here we show that although the traditional method of cryopreserving cells by slow cooling in the presence of 10% dimethyl sulfoxide (Me2SO) continues to be used by many, several novel MSC cryopreservation approaches have emerged. As in our previous review, we conclude from these recent reports that viable and functional MSCs from diverse tissues can be recovered after cryopreservation using a variety of cryoprotectants, freezing protocols, storage temperatures, and periods of storage. We also show that for logistical reasons there are now more studies devoted to the cryopreservation of tissues from which MSCs are derived. A new topic included in this review covers the application in COVID-19 of MSCs arising from their immunomodulatory and antiviral properties. Due to the inherent heterogeneity in MSC populations from different sources there is still no standardized procedure for their isolation, identification, functional characterization, cryopreservation, and route of administration, and not likely to be a "one-size-fits-all" approach in their applications in cell-based therapy and regenerative medicine.
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Affiliation(s)
- Leah A Marquez-Curtis
- Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB, Canada, T6G 1H9; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada, T6G 1C9
| | - Janet A W Elliott
- Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB, Canada, T6G 1H9; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada, T6G 1C9.
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Orimoto A, Addison WN, Mochizuki S, Ariyoshi W, Ono K, Kitamura C, Kiyono T, Fukuda T. Controlled cell proliferation and immortalization of human dental pulp stem cells with a doxycycline-inducible expression system. Cell Biochem Funct 2024; 42:e4064. [PMID: 38807466 DOI: 10.1002/cbf.4064] [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: 02/20/2024] [Revised: 05/12/2024] [Accepted: 05/18/2024] [Indexed: 05/30/2024]
Abstract
Human dental pulp stem cells are a potentially useful resource for cell-based therapies and tissue repair in dental and medical applications. However, the primary culture of isolated dental pulp stem cells has notably been limited. A major requirement of an ideal human dental pulp stem cell culture system is the preservation of efficient proliferation and innate stemness over prolonged passaging, while also ensuring ease of handling through standard, user-friendly culture methods. In this study, we have engineered a novel human dental pulp stem cell line, distinguished by the constitutive expression of telomerase reverse transcriptase (TERT), and the conditional expression of the R24C mutant cyclin-dependent kinase 4 (CDK4R24C) and Cyclin D1. We have named this cell line Tet-off K4DT hDPSCs. Furthermore, we have conducted a comprehensive comparative analysis of their biological attributes in relation to a previously immortalized human dental pulp stem cells, hDPSC-K4DT, which were immortalized by the constitutive expression of CDK4R24C, Cyclin D1 and TERT. In Tet-off K4DT cells, the expression of the K4D genes can be precisely suppressed by the inclusion of doxycycline. Remarkably, Tet-off K4DT cells demonstrated an extended cellular lifespan, increased proliferative capacity, and enhanced osteogenic differentiation potential when compared to K4DT cells. Moreover, Tet-off K4DT cells had no observable genomic aberrations and also displayed a sustained expression of stem cell markers even at relatively advanced passages. Taken together, the establishment of this new cell line holds immense promise as powerful experimental tool for both fundamental and applied research involving dental pulp stem cells.
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Affiliation(s)
- Ai Orimoto
- Division of Endodontics and Restorative Dentistry, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - William N Addison
- Division of Molecular Signaling and Biochemistry, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Shinichi Mochizuki
- Department of Chemistry and Biochemistry, The University of Kitakyushu, Kitakyushu, Fukuoka, Japan
| | - Wataru Ariyoshi
- Division of Infections and Molecular Biology, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Kentaro Ono
- Division of Physiology, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Chiaki Kitamura
- Division of Endodontics and Restorative Dentistry, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Tohru Kiyono
- Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan
| | - Tomokazu Fukuda
- Graduate School of Science and Engineering, Iwate University, Morioka, Iwate, Japan
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Siewe N, Friedman A. Osteoporosis induced by cellular senescence: A mathematical model. PLoS One 2024; 19:e0303978. [PMID: 38805428 PMCID: PMC11132490 DOI: 10.1371/journal.pone.0303978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 05/03/2024] [Indexed: 05/30/2024] Open
Abstract
Osteoporosis is a disease characterized by loss of bone mass, where bones become fragile and more likely to fracture. Bone density begins to decrease at age 50, and a state of osteoporosis is defined by loss of more than 25%. Cellular senescence is a permanent arrest of normal cell cycle, while maintaining cell viability. The number of senescent cells increase with age. Since osteoporosis is an aging disease, it is natural to consider the question to what extend senescent cells induce bone density loss and osteoporosis. In this paper we use a mathematical model to address this question. We determine the percent of bone loss for men and women during age 50 to 100 years, and the results depend on the rate η of net formation of senescent cell, with η = 1 being the average rate. In the case η = 1, the model simulations are in agreement with empirical data. We also consider senolytic drugs, like fisetin and quercetin, that selectively eliminate senescent cells, and assess their efficacy in terms of reducing bone loss. For example, at η = 1, with estrogen hormonal therapy and early treatment with fisetin, bone density loss for women by age 75 is 23.4% (below osteoporosis), while with no treatment with fisetin it is 25.8% (osteoporosis); without even a treatment with estrogen hormonal therapy, bone loss of 25.3% occurs already at age 65.
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Affiliation(s)
- Nourridine Siewe
- School of Mathematics and Statistics, College of Science, Rochester Institute of Technology, Rochester, New York, United States of America
| | - Avner Friedman
- Department of Mathematics, The Ohio State University, Columbus, Ohio, United States of America
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11
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Rendra E, Crigna AT, Daniele C, Sticht C, Cueppers M, Kluth MA, Ganss C, Frank MH, Gretz N, Bieback K. Clinical-grade human skin-derived ABCB5+ mesenchymal stromal cells exert anti-apoptotic and anti-inflammatory effects in vitro and modulate mRNA expression in a cisplatin-induced kidney injury murine model. Front Immunol 2024; 14:1228928. [PMID: 38274791 PMCID: PMC10808769 DOI: 10.3389/fimmu.2023.1228928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 12/22/2023] [Indexed: 01/27/2024] Open
Abstract
Acute kidney injury (AKI) is characterized by a rapid reduction in renal function and glomerular filtration rate (GFR). The broadly used anti-cancer chemotherapeutic agent cisplatin often induces AKI as an adverse drug side effect. Therapies targeted at the reversal of AKI and its potential progression to chronic kidney disease or end-stage renal disease are currently insufficiently effective. Mesenchymal stromal cells (MSCs) possess diverse immunomodulatory properties that confer upon them significant therapeutic potential for the treatment of diverse inflammatory disorders. Human dermal MSCs expressing ATP-Binding Cassette member B5 (ABCB5) have shown therapeutic efficacy in clinical trials in chronic skin wounds or recessive dystrophic epidermolysis bullosa. In preclinical studies, ABCB5+ MSCs have also shown to reverse metabolic reprogramming in polycystic kidney cells, suggesting a capacity for this cell subset to improve also organ function in kidney diseases. Here, we aimed to explore the therapeutic capacity of ABCB5+ MSCs to improve renal function in a preclinical rat model of cisplatin-induced AKI. First, the anti-apoptotic and immunomodulatory capacity was compared against research-grade adipose stromal cells (ASCs). Then, cross-species immunomodulatory capacity was checked, testing first inhibition of mitogen-driven peripheral blood mononuclear cells and then modulation of macrophage function. Finally, therapeutic efficacy was evaluated in a cisplatin AKI model. First, ABCB5+ MSCs suppressed cisplatin-induced apoptosis of human conditionally-immortalized proximal tubular epithelial cells in vitro, most likely by reducing oxidative stress. Second, ABCB5+ MSCs inhibited the proliferation of either human or rat peripheral blood mononuclear cells, in the human system via the Indoleamine/kynurenine axis and in the murine context via nitric oxide/nitrite. Third, ABCB5+ MSCs decreased TNF-α secretion after lipopolysaccharide stimulation and modulated phagocytosis and in both human and rat macrophages, involving prostaglandin E2 and TGF-β1, respectively. Fourth, clinical-grade ABCB5+ MSCs grafted intravenously and intraperitoneally to a cisplatin-induced AKI murine model exerted modulatory effects on mRNA expression patterns toward an anti-inflammatory and pro-regenerative state despite an apparent lack of amelioration of renal damage at physiologic, metabolic, and histologic levels. Our results demonstrate anti-inflammatory and pro-regenerative effects of clinical grade ABCB5+ MSCs in vitro and in vivo and suggest potential therapeutic utility of this cell population for treatment or prevention of cisplatin chemotherapy-induced tissue toxicity.
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Affiliation(s)
- Erika Rendra
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service Baden-Württemberg - Hessen, Mannheim, Germany
| | - Adriana Torres Crigna
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service Baden-Württemberg - Hessen, Mannheim, Germany
| | - Cristina Daniele
- Medical Faculty Mannheim, Medical Research Centre, Heidelberg University, Mannheim, Germany
| | - Carsten Sticht
- Medical Faculty Mannheim, Medical Research Centre, Heidelberg University, Mannheim, Germany
| | - Maike Cueppers
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service Baden-Württemberg - Hessen, Mannheim, Germany
| | | | | | - Markus H. Frank
- Transplant Research Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, United States
- Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women’s Hospital, Boston, MA, United States
- School of Medical and Health Sciences, Edith Cowan University, Perth, WA, Australia
| | - Norbert Gretz
- Medical Faculty Mannheim, Medical Research Centre, Heidelberg University, Mannheim, Germany
| | - Karen Bieback
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service Baden-Württemberg - Hessen, Mannheim, Germany
- Mannheim Institute for Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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12
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Garcia Gómez-Heras S, Garcia-Arranz M, Vega-Clemente L, Olivera-Salazar R, Vélez Pinto JF, Fernández-García M, Guadalajara H, Yáñez R, Garcia-Olmo D. Study of the Effect of Wild-Type and Transiently Expressing CXCR4 and IL-10 Mesenchymal Stromal Cells in a Mouse Model of Peritonitis. Int J Mol Sci 2023; 25:520. [PMID: 38203690 PMCID: PMC10778615 DOI: 10.3390/ijms25010520] [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: 11/21/2023] [Revised: 12/19/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
Sepsis due to peritonitis is a process associated with an inflammatory state. Mesenchymal stromal cells (MSCs) modulate the immune system due to the paracrine factors released and may be a therapeutic alternative. Three treatment groups were developed in a murine model of peritonitis to verify the effect of human adipose mesenchymal stem cell (hASCs). Additionally, a temporary modification was carried out on them to improve their arrival in inflamed tissues (CXCR4), as well as their anti-inflammatory activity (IL-10). The capacity to reduce systemic inflammation was studied using a local application (peritoneal injection) as a treatment route. Comparisons involving the therapeutic effect of wild-type ASCs and ASCs transiently expressing CXCR4 and IL-10 were carried out with the aim of generating an improved anti-inflammatory response for sepsis in addition to standard antibiotic treatment. However, under the experimental conditions used in these studies, no differences were found between both groups with ASCs. The peritoneal administration of hASCs or genetically modified hASCs constitutes an efficient and safe therapy in our model of mouse peritonitis.
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Affiliation(s)
- Soledad Garcia Gómez-Heras
- Department of Basic Health Science, Faculty of Health Sciences, Rey Juan Carlos University, 28922 Alcorcón, Spain
| | - Mariano Garcia-Arranz
- New Therapy Laboratory, Health Research Institute Fundación Jiménez Díaz, 28033 Madrid, Spain; (L.V.-C.); (R.O.-S.); (H.G.); (D.G.-O.)
- Department of Surgery, Faculty of Medicine, Universidad Autónoma de Madrid, 28029 Madrid, Spain;
| | - Luz Vega-Clemente
- New Therapy Laboratory, Health Research Institute Fundación Jiménez Díaz, 28033 Madrid, Spain; (L.V.-C.); (R.O.-S.); (H.G.); (D.G.-O.)
| | - Rocio Olivera-Salazar
- New Therapy Laboratory, Health Research Institute Fundación Jiménez Díaz, 28033 Madrid, Spain; (L.V.-C.); (R.O.-S.); (H.G.); (D.G.-O.)
| | - Juan Felipe Vélez Pinto
- Department of Surgery, Faculty of Medicine, Universidad Autónoma de Madrid, 28029 Madrid, Spain;
| | - María Fernández-García
- Biomedical Innovation Unit, Division of Hematopoietic Innovative Therapies, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas (CIEMAT), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM), 28040 Madrid, Spain; (M.F.-G.); (R.Y.)
| | - Héctor Guadalajara
- New Therapy Laboratory, Health Research Institute Fundación Jiménez Díaz, 28033 Madrid, Spain; (L.V.-C.); (R.O.-S.); (H.G.); (D.G.-O.)
- Surgery Department, Fundación Jiménez Díaz University Hospital, 28033 Madrid, Spain
| | - Rosa Yáñez
- Biomedical Innovation Unit, Division of Hematopoietic Innovative Therapies, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas (CIEMAT), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD, UAM), 28040 Madrid, Spain; (M.F.-G.); (R.Y.)
| | - Damian Garcia-Olmo
- New Therapy Laboratory, Health Research Institute Fundación Jiménez Díaz, 28033 Madrid, Spain; (L.V.-C.); (R.O.-S.); (H.G.); (D.G.-O.)
- Department of Surgery, Faculty of Medicine, Universidad Autónoma de Madrid, 28029 Madrid, Spain;
- Surgery Department, Fundación Jiménez Díaz University Hospital, 28033 Madrid, Spain
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13
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Denoeud C, Luo G, Paquet J, Boisselier J, Wosinski P, Moya A, Diallo A, Larochette N, Marinesco S, Meiller A, Becquart P, Moussi H, Vilquin JT, Logeart-Avramoglou D, Gand A, Larreta-Garde V, Pauthe E, Potier E, Petite H. Enzyme-controlled, nutritive hydrogel for mesenchymal stromal cell survival and paracrine functions. Commun Biol 2023; 6:1266. [PMID: 38092861 PMCID: PMC10719273 DOI: 10.1038/s42003-023-05643-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 11/28/2023] [Indexed: 12/17/2023] Open
Abstract
Culture-adapted human mesenchymal stromal cells (hMSCs) are appealing candidates for regenerative medicine applications. However, these cells implanted in lesions as single cells or tissue constructs encounter an ischemic microenvironment responsible for their massive death post-transplantation, a major roadblock to successful clinical therapies. We hereby propose a paradigm shift for enhancing hMSC survival by designing, developing, and testing an enzyme-controlled, nutritive hydrogel with an inbuilt glucose delivery system for the first time. This hydrogel, composed of fibrin, starch (a polymer of glucose), and amyloglucosidase (AMG, an enzyme that hydrolyze glucose from starch), provides physiological glucose levels to fuel hMSCs via glycolysis. hMSCs loaded in these hydrogels and exposed to near anoxia (0.1% pO2) in vitro exhibited improved cell viability and angioinductive functions for up to 14 days. Most importantly, these nutritive hydrogels promoted hMSC viability and paracrine functions when implanted ectopically. Our findings suggest that local glucose delivery via the proposed nutritive hydrogel can be an efficient approach to improve hMSC-based therapeutic efficacy.
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Affiliation(s)
- Cyprien Denoeud
- University Paris Cité, CNRS, INSERM, ENVA, B3OA, Paris, France
| | - Guotian Luo
- University Paris Cité, CNRS, INSERM, ENVA, B3OA, Paris, France
| | - Joseph Paquet
- University Paris Cité, CNRS, INSERM, ENVA, B3OA, Paris, France
| | - Julie Boisselier
- Biomaterial for Health Group, ERRMECe, University of Cergy-Pontoise, Cergy-Pontoise, France
| | | | - Adrien Moya
- University Paris Cité, CNRS, INSERM, ENVA, B3OA, Paris, France
| | - Ahmad Diallo
- University Paris Cité, CNRS, INSERM, ENVA, B3OA, Paris, France
| | | | | | - Anne Meiller
- Neuroscience Research Center, AniRA-NeuroChem Platform, Lyon, France
| | - Pierre Becquart
- University Paris Cité, CNRS, INSERM, ENVA, B3OA, Paris, France
| | - Hilel Moussi
- University Paris Cité, CNRS, INSERM, ENVA, B3OA, Paris, France
| | - Jean-Thomas Vilquin
- Sorbonne Université, INSERM, AIM, CNRS, Centre de Recherche en Myologie, Hôpital Pitié Salpêtrière, Paris, France
| | | | - Adeline Gand
- Biomaterial for Health Group, ERRMECe, University of Cergy-Pontoise, Cergy-Pontoise, France
| | | | - Emmanuel Pauthe
- Biomaterial for Health Group, ERRMECe, University of Cergy-Pontoise, Cergy-Pontoise, France
| | - Esther Potier
- University Paris Cité, CNRS, INSERM, ENVA, B3OA, Paris, France
| | - Hervé Petite
- University Paris Cité, CNRS, INSERM, ENVA, B3OA, Paris, France.
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14
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Vélez-Pinto JF, Garcia-Arranz M, García-Bernal D, García Gómez-Heras S, Villarejo-Campos P, García-Hernández AM, Vega-Clemente L, Jiménez-Galanes S, Guadalajara H, Moraleda JM, García-Olmo D. Therapeutic effect of adipose-derived mesenchymal stem cells in a porcine model of abdominal sepsis. Stem Cell Res Ther 2023; 14:365. [PMID: 38087374 PMCID: PMC10717819 DOI: 10.1186/s13287-023-03588-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND The term sepsis refers to a complex and heterogeneous syndrome. Although great progress has been made in improving the diagnosis and treatment of this condition, it continues to have a huge impact on morbidity and mortality worldwide. Mesenchymal stem cells are a population of multipotent cells that have immunomodulatory properties, anti-apoptotic effects, and antimicrobial activity. We studied these capacities in a porcine model of peritoneal sepsis. METHODS We infused human adipose-derived mesenchymal stem cells (ADSCs) into a porcine model of peritoneal sepsis. Twenty piglets were treated with antibiotics alone (control group) or antibiotics plus peritoneal infusion of ADSCs at a concentration of 2 × 106 cells/kg or 4 × 106 cells/kg (low- and high-dose experimental groups, respectively). The animals were evaluated at different time points to determine their clinical status, biochemical and hematologic parameters, presence of inflammatory cytokines and chemokines in blood and peritoneal fluid, and finally by histologic analysis of the organs of the peritoneal cavity. RESULTS One day after sepsis induction, all animals presented peritonitis with bacterial infection as well as elevated C-reactive protein, haptoglobin, IL-1Ra, IL-6, and IL-1b. Xenogeneic ADSC infusion did not elicit an immune response, and peritoneal administration of the treatment was safe and feasible. One day after infusion, the two experimental groups showed a superior physical condition (e.g., mobility, feeding) and a significant increase of IL-10 and TGF-β in blood and a decrease of IL-1Ra, IL-1b, and IL-6. After 7 days, all animals treated with ADSCs had better results concerning blood biomarkers, and histopathological analysis revealed a lower degree of inflammatory cell infiltration of the organs of the peritoneal cavity. CONCLUSIONS Intraperitoneal administration of ADSCs as an adjuvant therapy for sepsis improves the outcome and diminishes the effects of peritonitis and associated organ damage by regulating the immune system and reducing intra-abdominal adhesions in a clinically relevant porcine model of abdominal sepsis.
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Affiliation(s)
- J F Vélez-Pinto
- Surgery Department, Fundación Jiménez Díaz University Hospital, 28033, Madrid, Spain
| | - M Garcia-Arranz
- New Therapy Laboratory, Health Research Institute of the Jimenez Diaz Foundation (Instituto de Investigacion Sanitaria de la Fundacion Jimenez Diaz), Avda Reyes Católicos 2, 28040, Madrid, Spain.
- Department of Surgery, Faculty of Medicine, Universidad Autónoma de Madrid, 28029, Madrid, Spain.
| | - D García-Bernal
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Virgen de la Arrixaca University Hospital, University of Murcia, Murcia, Spain
- Biochemistry, Molecular Biology and Immunology Department, Faculty of Medicine, University of Murcia, Murcia, Spain
| | - S García Gómez-Heras
- Department of Basic Health Science, Faculty of Health Sciences, Rey Juan Carlos University, 28922, Alcorcón, Madrid, Spain
| | - P Villarejo-Campos
- Surgery Department, Fundación Jiménez Díaz University Hospital, 28033, Madrid, Spain
| | - A M García-Hernández
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Virgen de la Arrixaca University Hospital, University of Murcia, Murcia, Spain
| | - L Vega-Clemente
- New Therapy Laboratory, Health Research Institute of the Jimenez Diaz Foundation (Instituto de Investigacion Sanitaria de la Fundacion Jimenez Diaz), Avda Reyes Católicos 2, 28040, Madrid, Spain
| | - S Jiménez-Galanes
- Department of Surgery, Infanta Elena University Hospital, 28342, Valdemoro, Madrid, Spain
| | - H Guadalajara
- Surgery Department, Fundación Jiménez Díaz University Hospital, 28033, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Universidad Autónoma de Madrid, 28029, Madrid, Spain
| | - J M Moraleda
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Virgen de la Arrixaca University Hospital, University of Murcia, Murcia, Spain
| | - D García-Olmo
- Surgery Department, Fundación Jiménez Díaz University Hospital, 28033, Madrid, Spain
- New Therapy Laboratory, Health Research Institute of the Jimenez Diaz Foundation (Instituto de Investigacion Sanitaria de la Fundacion Jimenez Diaz), Avda Reyes Católicos 2, 28040, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Universidad Autónoma de Madrid, 28029, Madrid, Spain
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15
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Watts AE. Use of Stem Cells for the Treatment of Musculoskeletal Injuries in Horses. Vet Clin North Am Equine Pract 2023; 39:475-487. [PMID: 37625917 DOI: 10.1016/j.cveq.2023.07.003] [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: 08/27/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are used as a regenerative therapy in horses for musculoskeletal injury since the late 1990s and in some regions are standard of care for certain injuries. Yet, there is no Food and Drug Administration-approved MSC therapeutic in the United States for horses. In humans, lack of regulatory approval in the United States has been caused by failure of late-phase clinical trials to demonstrate consistent efficacy, perhaps because of nonuniformity of MSC preparation and application techniques. This article discusses clinical evidence for musculoskeletal applications of MSCs in the horse and current challenges to marketing approval.
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16
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Kresse JC, Gregersen E, Atay JCL, Eijken M, Nørregaard R. Does the route matter? A preclinical review of mesenchymal stromal cell delivery to the kidney. APMIS 2023; 131:687-697. [PMID: 37750005 DOI: 10.1111/apm.13352] [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: 09/01/2023] [Accepted: 09/08/2023] [Indexed: 09/27/2023]
Abstract
Mesenchymal stromal/stem cell (MSC) therapy has been thoroughly tested in preclinical animal models and holds great promise for the treatment of kidney diseases. It is becoming increasingly evident that the efficacy of MSC therapy is dependent on several factors including dosage, the tissue source of MSCs, the route of delivery and timing of administration. In a time where MSC therapy is moving from preclinical research to clinically therapeutic use, the importance of choice of delivery method, modality, and administration route increases. In this review, we provide an overview of the different MSC delivery routes used in preclinical kidney disease models, highlight the recent advances in the field, and summarize studies comparing delivery routes of MSCs to the kidney.
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Affiliation(s)
| | - Emil Gregersen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | | | - Marco Eijken
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Rikke Nørregaard
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
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17
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Trevizani M, Leal LL, Rettore JVP, Macedo GC, Alves CCDS, de Castro SBR, do Carmo AMR, da Silva SA, Maranduba CMDC, Silva FDS. Tumor necrosis factor α, and agonist and antagonists of cannabinoid receptor type 1 and type 2 alter the immunophenotype of stem cells from human exfoliated deciduous teeth. EINSTEIN-SAO PAULO 2023; 21:eAO0405. [PMID: 37970951 PMCID: PMC10631756 DOI: 10.31744/einstein_journal/2023ao0405] [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: 12/01/2022] [Accepted: 03/19/2023] [Indexed: 11/19/2023] Open
Abstract
OBJECTIVE To verify the involvement of the endocannabinoid system in the immunomodulatory profile of stem cells from human exfoliated deciduous teeth, in the presence or absence of TNF-α, and agonist and antagonists of CB1 and CB2. METHODS Stem cells from human exfoliated deciduous teeth were cultured in the presence or absence of an agonist, anandamide, and two antagonists, AM251 and SR144528, of CB1 and CB2 receptors, with or without TNF-α stimulation. For analysis of immunomodulation, surface molecules linked to immunomodulation, namely human leukocyte antigen-DR isotype (HLA-DR), and programmed death ligands 1 (PD-L1) and 2 (PD-L2) were measured using flow cytometry. RESULTS The inhibition of endocannabinoid receptors together with the proinflammatory effect of TNF-α resulted in increased HLA-DR expression in stem cells from human exfoliated deciduous teeth, as well as, in these cells acquiring an anti-inflammatory profile by enhancing the expression of PD-L1 and PD-L2. CONCLUSION Stem cells from human exfoliated deciduous teeth respond to the endocannabinoid system and TNF-α by altering key immune response molecules. Inhibition of endocannabinoid receptors and TNF-α led to an increase in HLA-DR, PD-L1, and PD-L2 levels in stem cells from human exfoliated deciduous teeth. This study shows the interaction between mesenchymal stromal cells and the immune and endocannabinoid systems.
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Affiliation(s)
- Marizia Trevizani
- Instituto de Ciências BiológicasUniversidade Federal de Juiz de ForaJuiz de ForaMGBrazil Instituto de Ciências Biológicas , Universidade Federal de Juiz de Fora , Juiz de Fora , MG , Brazil .
| | - Laís Lopardi Leal
- Instituto de Ciências BiológicasUniversidade Federal de Juiz de ForaJuiz de ForaMGBrazil Instituto de Ciências Biológicas , Universidade Federal de Juiz de Fora , Juiz de Fora , MG , Brazil .
| | - João Vitor Paes Rettore
- Instituto de Ciências BiológicasUniversidade Federal de Juiz de ForaJuiz de ForaMGBrazil Instituto de Ciências Biológicas , Universidade Federal de Juiz de Fora , Juiz de Fora , MG , Brazil .
| | - Gilson Costa Macedo
- Instituto de Ciências BiológicasUniversidade Federal de Juiz de ForaJuiz de ForaMGBrazil Instituto de Ciências Biológicas , Universidade Federal de Juiz de Fora , Juiz de Fora , MG , Brazil .
| | - Caio César de Souza Alves
- Faculdade de Medicina do MucuriUniversidade Federal dos Vales do Jequitinhonha e MucuriTeófilo OtoniMGBrazil Faculdade de Medicina do Mucuri , Universidade Federal dos Vales do Jequitinhonha e Mucuri , Teófilo Otoni , MG , Brazil .
| | - Sandra Bertelli Ribeiro de Castro
- Faculdade de Medicina do MucuriUniversidade Federal dos Vales do Jequitinhonha e MucuriTeófilo OtoniMGBrazil Faculdade de Medicina do Mucuri , Universidade Federal dos Vales do Jequitinhonha e Mucuri , Teófilo Otoni , MG , Brazil .
| | - Antônio Márcio Resende do Carmo
- Instituto de Ciências BiológicasUniversidade Federal de Juiz de ForaJuiz de ForaMGBrazil Instituto de Ciências Biológicas , Universidade Federal de Juiz de Fora , Juiz de Fora , MG , Brazil .
| | - Silvioney Augusto da Silva
- Instituto de Ciências BiológicasUniversidade Federal de Juiz de ForaJuiz de ForaMGBrazil Instituto de Ciências Biológicas , Universidade Federal de Juiz de Fora , Juiz de Fora , MG , Brazil .
| | - Carlos Magno da Costa Maranduba
- Instituto de Ciências BiológicasUniversidade Federal de Juiz de ForaJuiz de ForaMGBrazil Instituto de Ciências Biológicas , Universidade Federal de Juiz de Fora , Juiz de Fora , MG , Brazil .
| | - Fernando de Sá Silva
- Universidade Federal de Juiz de ForaGovernador ValadaresMGBrazil Universidade Federal de Juiz de Fora , Governador Valadares , MG , Brazil .
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Zaripova LN, Midgley A, Christmas SE, Beresford MW, Pain C, Baildam EM, Oldershaw RA. Mesenchymal Stem Cells in the Pathogenesis and Therapy of Autoimmune and Autoinflammatory Diseases. Int J Mol Sci 2023; 24:16040. [PMID: 38003230 PMCID: PMC10671211 DOI: 10.3390/ijms242216040] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/27/2023] [Accepted: 10/31/2023] [Indexed: 11/26/2023] Open
Abstract
Mesenchymal stem cells (MSCs) modulate immune responses and maintain self-tolerance. Their trophic activities and regenerative properties make them potential immunosuppressants for treating autoimmune and autoinflammatory diseases. MSCs are drawn to sites of injury and inflammation where they can both reduce inflammation and contribute to tissue regeneration. An increased understanding of the role of MSCs in the development and progression of autoimmune disorders has revealed that MSCs are passive targets in the inflammatory process, becoming impaired by it and exhibiting loss of immunomodulatory activity. MSCs have been considered as potential novel cell therapies for severe autoimmune and autoinflammatory diseases, which at present have only disease modifying rather than curative treatment options. MSCs are emerging as potential therapies for severe autoimmune and autoinflammatory diseases. Clinical application of MSCs in rare cases of severe disease in which other existing treatment modalities have failed, have demonstrated potential use in treating multiple diseases, including rheumatoid arthritis, systemic lupus erythematosus, myocardial infarction, liver cirrhosis, spinal cord injury, multiple sclerosis, and COVID-19 pneumonia. This review explores the biological mechanisms behind the role of MSCs in autoimmune and autoinflammatory diseases. It also covers their immunomodulatory capabilities, potential therapeutic applications, and the challenges and risks associated with MSC therapy.
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Affiliation(s)
- Lina N. Zaripova
- Institute of Fundamental and Applied Medicine, National Scientific Medical Center, 42 Abylai Khan Avenue, Astana 010000, Kazakhstan;
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK
| | - Angela Midgley
- Department of Women and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Institute in the Park, Alder Hey Children’s NHS Foundation Trust, Liverpool L14 5AB, UK; (A.M.); (M.W.B.); (C.P.)
| | - Stephen E. Christmas
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, Faculty of Health and Life Sciences, University of Liverpool, The Ronald Ross Building, 8 West Derby Street, Liverpool L69 7BE, UK;
| | - Michael W. Beresford
- Department of Women and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Institute in the Park, Alder Hey Children’s NHS Foundation Trust, Liverpool L14 5AB, UK; (A.M.); (M.W.B.); (C.P.)
- Department of Paediatric Rheumatology, Alder Hey Children’s NHS Foundation Trust, East Prescott Road, Liverpool L14 5AB, UK
| | - Clare Pain
- Department of Women and Children’s Health, Institute of Life Course and Medical Sciences, University of Liverpool, Institute in the Park, Alder Hey Children’s NHS Foundation Trust, Liverpool L14 5AB, UK; (A.M.); (M.W.B.); (C.P.)
- Department of Paediatric Rheumatology, Alder Hey Children’s NHS Foundation Trust, East Prescott Road, Liverpool L14 5AB, UK
| | - Eileen M. Baildam
- Department of Paediatric Rheumatology, The Alexandra Hospital, Mill Lane, Cheadle SK8 2PX, UK;
| | - Rachel A. Oldershaw
- Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK
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19
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Schwarzl T, Keogh A, Shaw G, Krstic A, Clayton E, Higgins DG, Kolch W, Barry F. Transcriptional profiling of early differentiation of primary human mesenchymal stem cells into chondrocytes. Sci Data 2023; 10:758. [PMID: 37923731 PMCID: PMC10624874 DOI: 10.1038/s41597-023-02686-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 10/25/2023] [Indexed: 11/06/2023] Open
Abstract
Articular cartilage has only very limited regenerative capacities in humans. Tissue engineering techniques for cartilage damage repair are limited in the production of hyaline cartilage. Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells and can be differentiated into mature cartilage cells, chondrocytes, which could be used for repairing damaged cartilage. Chondrogenesis is a highly complex, relatively inefficient process lasting over 3 weeks in vitro. Methods: In order to better understand chondrogenic differentiation, especially the commitment phase, we have performed transcriptional profiling of MSC differentiation into chondrocytes from early timepoints starting 15 minutes after induction to 16 hours and fully differentiated chondrocytes at 21 days in triplicates.
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Affiliation(s)
- Thomas Schwarzl
- European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117, Heidelberg, Germany
| | - Andrea Keogh
- Previously: Regenerative Medicine Institute (REMEDI), Biosciences, National University of Ireland Galway, University Road, Galway, Ireland
| | - Georgina Shaw
- Regenerative Medicine Institute (REMEDI), Biosciences, National University of Ireland Galway, University Road, Galway, Ireland
| | - Aleksandar Krstic
- Systems Biology Ireland (SBI), School of Medicine, University College Dublin, Dublin, 4, Ireland
| | - Elizabeth Clayton
- Previously: Regenerative Medicine Institute (REMEDI), Biosciences, National University of Ireland Galway, University Road, Galway, Ireland
| | - Desmond G Higgins
- Systems Biology Ireland (SBI), School of Medicine, University College Dublin, Dublin, 4, Ireland
- Conway Institute of Biomolecular and Biomedical Research, University College Dublin (UCD), Belfield, Dublin, 4, Ireland
| | - Walter Kolch
- Systems Biology Ireland (SBI), School of Medicine, University College Dublin, Dublin, 4, Ireland.
- Conway Institute of Biomolecular and Biomedical Research, University College Dublin (UCD), Belfield, Dublin, 4, Ireland.
| | - Frank Barry
- Regenerative Medicine Institute (REMEDI), Biosciences, National University of Ireland Galway, University Road, Galway, Ireland
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20
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Litvinov IK, Belyaeva TN, Salova AV, Aksenov ND, Chelushkin PS, Solomatina AI, Tunik SP, Kornilova ES. The Dual Luminescence Lifetime pH/Oxygen Sensor: Evaluation of Applicability for Intravital Analysis of 2D- and 3D-Cultivated Human Endometrial Mesenchymal Stromal Cells. Int J Mol Sci 2023; 24:15606. [PMID: 37958592 PMCID: PMC10650141 DOI: 10.3390/ijms242115606] [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: 09/14/2023] [Revised: 10/16/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
The oxygenation of cells and tissues and acidification of the cellular endolysosomal system are among the major factors that ensure normal functioning of an organism and are violated in various pathologies. Recording of these parameters and their changes under various conditions is an important task for both basic research and clinical applications. In the present work, we utilized internalizable dual pH/O2 lifetime sensor (Ir-HSA-FITC) based on the covalent conjugation of human serum albumin (HSA) with fluorescein isothiocyanate (FITC) as pH sensor and an orthometalated iridium complex as O2 sensor. The probe was tested for simultaneous detection of acidification level and oxygen concentration in endolysosomes of endometrial mesenchymal stem/stromal cells (enMSCs) cultivated as 2D monolayers and 3D spheroids. Using a combined FLIM/PLIM approach, we found that due to high autofluorescence of enMSCs FITC lifetime signal in control cells was insufficient to estimate pH changes. However, using flow cytometry and confocal microscopy, we managed to detect the FITC signal response to inhibition of endolysosomal acidification by Bafilomycin A1. The iridium chromophore phosphorescence was detected reliably by all methods used. It was demonstrated that the sensor, accumulated in endolysosomes for 24 h, disappeared from proliferating 2D enMSCs by 72 h, but can still be recorded in non-proliferating spheroids. PLIM showed high sensitivity and responsiveness of iridium chromophore phosphorescence to experimental hypoxia both in 2D and 3D cultures. In spheroids, the phosphorescence signal was detected at a depth of up to 60 μm using PLIM and showed a gradient in the intracellular O2 level towards their center.
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Affiliation(s)
- Ilia K. Litvinov
- Institute of Cytology, Russian Academy of Sciences, Tikhoretsky av. 4, 194064 Saint-Petersburg, Russia; (I.K.L.); (T.N.B.); (A.V.S.); (N.D.A.)
| | - Tatiana N. Belyaeva
- Institute of Cytology, Russian Academy of Sciences, Tikhoretsky av. 4, 194064 Saint-Petersburg, Russia; (I.K.L.); (T.N.B.); (A.V.S.); (N.D.A.)
| | - Anna V. Salova
- Institute of Cytology, Russian Academy of Sciences, Tikhoretsky av. 4, 194064 Saint-Petersburg, Russia; (I.K.L.); (T.N.B.); (A.V.S.); (N.D.A.)
| | - Nikolay D. Aksenov
- Institute of Cytology, Russian Academy of Sciences, Tikhoretsky av. 4, 194064 Saint-Petersburg, Russia; (I.K.L.); (T.N.B.); (A.V.S.); (N.D.A.)
| | - Pavel S. Chelushkin
- Institute of Chemistry, St. Petersburg State University, Universitetskii av., 26, 198504 Saint-Petersburg, Russia; (P.S.C.); (A.I.S.)
| | - Anastasia I. Solomatina
- Institute of Chemistry, St. Petersburg State University, Universitetskii av., 26, 198504 Saint-Petersburg, Russia; (P.S.C.); (A.I.S.)
| | - Sergey P. Tunik
- Institute of Chemistry, St. Petersburg State University, Universitetskii av., 26, 198504 Saint-Petersburg, Russia; (P.S.C.); (A.I.S.)
| | - Elena S. Kornilova
- Institute of Cytology, Russian Academy of Sciences, Tikhoretsky av. 4, 194064 Saint-Petersburg, Russia; (I.K.L.); (T.N.B.); (A.V.S.); (N.D.A.)
- Higher School of Biomedical Systems and Technologies, Peter the Great St. Petersburg Polytechnic University, Khlopina Str. 11, 195251 Saint-Petersburg, Russia
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21
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Rizano A, Margiana R, Supardi S, Narulita P. Exploring the future potential of mesenchymal stem/stromal cells and their derivatives to support assisted reproductive technology for female infertility applications. Hum Cell 2023; 36:1604-1619. [PMID: 37407748 DOI: 10.1007/s13577-023-00941-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 06/16/2023] [Indexed: 07/07/2023]
Abstract
Women's infertility impacts the quality of life of both patients and couples and has multifaceted dimensions that increase the number of challenges associated with female infertility and how to face them. Female reproductive disorders, such as premature ovarian failure (POF), endometriosis, Asherman syndrome (AS), polycystic ovary syndrome (PCOS), and preeclampsia, can stimulate infertility. In the last decade, translational medicine has advanced, and scientists are focusing on infertility therapy with innovative attitudes. Recent investigations have suggested that stem cell treatments could be safe and effective. Stem cell therapy has established a novel method for treating women's infertility as part of a regeneration approach. The chief properties and potential of mesenchymal stem/stromal cells (MSCs) in the future of women's infertility should be considered by researchers. Due to their high abundance, great ability to self-renew, and high differentiation capacity, as well as less ethical concerns, MSC-based therapy has been found to be an effective alternative strategy to the previous methods for treating female infertility, such as intrauterine insemination, in vitro fertilization, medicines, and surgical procedures. These types of stem cells exert their beneficial role by releasing active mediators, promoting cell homing, and contributing to immune modulation. Here we first provide an overview of MSCs and their crucial roles in both biological and immunological processes. The next large chapter covers current preclinical and clinical studies on the application of MSCs to treat various female reproductive disorders. Finally, we deliberate on the extant challenges that hinder the application of MSCs in female infertility and suggest plausible measures to alleviate these impediments.
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Affiliation(s)
- Andrew Rizano
- Department of Medical Biology, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Ria Margiana
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia.
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
- Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
- Indonesia General Academic Hospital, Depok, Indonesia.
- Ciptomangunkusumo General Academic Hospital, Jakarta, Indonesia.
| | - Supardi Supardi
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Pety Narulita
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
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22
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Valsecchi C, Croce S, Lenta E, Acquafredda G, Comoli P, Avanzini MA. TITLE: New therapeutic approaches in pediatric diseases: Mesenchymal stromal cell and mesenchymal stromal cell-derived extracellular vesicles as new drugs. Pharmacol Res 2023; 192:106796. [PMID: 37207738 DOI: 10.1016/j.phrs.2023.106796] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 05/12/2023] [Accepted: 05/16/2023] [Indexed: 05/21/2023]
Abstract
Mesenchymal Stromal Cell (MSC) clinical applications have been widely reported and their therapeutic potential has been documented in several diseases. MSCs can be isolated from several human tissues and easily expanded in vitro, they are able to differentiate in a variety of cell lineages, and they are known to interact with most immunological cells, showing immunosuppressive and tissue repair properties. Their therapeutic efficacy is closely associated with the release of bioactive molecules, namely Extracellular Vesicles (EVs), effective as their parental cells. EVs isolated from MSCs act by fusing with target cell membrane and releasing their content, showing a great potential for the treatment of injured tissues and organs, and for the modulation of the host immune system. EV-based therapies provide, as major advantages, the possibility to cross the epithelium and blood barrier and their activity is not influenced by the surrounding environment. In the present review, we deal with pre-clinical reports and clinical trials to provide data in support of MSC and EV clinical efficacy with particular focus on neonatal and pediatric diseases. Considering pre-clinical and clinical data so far available, it is likely that cell-based and cell-free therapies could become an important therapeutic approach for the treatment of several pediatric diseases.
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Affiliation(s)
- Chiara Valsecchi
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Stefania Croce
- Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Elisa Lenta
- Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Gloria Acquafredda
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Patrizia Comoli
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
| | - Maria Antonietta Avanzini
- Pediatric Hematology Oncology Unit and Cell Factory, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
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23
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Uwazie CC, Faircloth TU, Parr RN, Reddy YU, Hematti P, Rajan D, Chinnadurai R. Contrariety of Human Bone Marrow Mesenchymal Stromal Cell Functionality in Modulating Circulatory Myeloid and Plasmacytoid Dendritic Cell Subsets. BIOLOGY 2023; 12:biology12050725. [PMID: 37237538 DOI: 10.3390/biology12050725] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/10/2023] [Accepted: 05/12/2023] [Indexed: 05/28/2023]
Abstract
Mesenchymal Stromal Cells (MSCs) derived from bone marrow are widely tested in clinical trials as a cellular therapy for potential inflammatory disorders. The mechanism of action of MSCs in mediating immune modulation is of wide interest. In the present study, we investigated the effect of human bone-marrow-derived MSCs in modulating the circulating peripheral blood dendritic cell responses through flow cytometry and multiplex secretome technology upon their coculture ex vivo. Our results demonstrated that MSCs do not significantly modulate the responses of plasmacytoid dendritic cells. However, MSCs dose-dependently promote the maturation of myeloid dendritic cells. Mechanistic analysis showed that dendritic cell licensing cues (Lipopolysaccharide and Interferon-gamma) stimulate MSCs to secret an array of dendritic cell maturation-associated secretory factors. We also identified that MSC-mediated upregulation of myeloid dendritic cell maturation is associated with the unique predictive secretome signature. Overall, the present study demonstrated the dichotomy of MSC functionality in modulating myeloid and plasmacytoid dendritic cells. This study provides clues that clinical trials need to investigate if circulating dendritic cell subsets in MSC therapy can serve as potency biomarkers.
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Affiliation(s)
- Crystal C Uwazie
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31324, USA
| | - Tyler U Faircloth
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31324, USA
| | - Rhett N Parr
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31324, USA
| | - Yenamala U Reddy
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31324, USA
| | - Peiman Hematti
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Devi Rajan
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31324, USA
| | - Raghavan Chinnadurai
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31324, USA
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24
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Khadivi F, Mojaverrostami S, Ramesh M, Rastegar T, Abbasi Y, Bashiri Z. Protective effects of human amniotic membrane derived mesenchymal stem cells (hAMSCs) secreted factors on mouse spermatogenesis and sperm chromatin condensation following unilateral testicular torsion. Ann Anat 2023; 249:152084. [PMID: 36972855 DOI: 10.1016/j.aanat.2023.152084] [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: 06/26/2022] [Revised: 01/29/2023] [Accepted: 03/06/2023] [Indexed: 03/29/2023]
Abstract
Testicular torsion is considered a urological disorder that requires immediate detorsion surgery. Ischemia/reperfusion (I/R) injury after testicular torsion detorsion causes of drastic impairment of spermatogenesis and infertility. Cell-free-based approaches seem to be a promising strategy to prevent I/R injury, they have more stable biological properties, and they contain paracrine factors of mesenchymal stem cells. The purpose of this study was to evaluate the protective effects of human amniotic membrane derived mesenchymal stem cells (hAMSCs) secreted factors on mouse sperm chromatin condensation and spermatogenesis improvement after I/R injury. hAMSCs were isolated and characterized by RT- PCR and flow cytometry, preparation of hAMSCs secreted factors was performed. Forty male mice were randomly divided into 4 groups: sham-operated, torsion detorsion, torsion detorsion+ intratesticular injection of DMEM/F-12, and torsion detorsion+ intratesticular injection of hAMSCs secreted factors. After one cycle of spermatogenesis, the mean number of germ cells, Sertoli, Leydig, myoid as well as tubular parameters, Johnson score, and spermatogenesis indexes were evaluated by H& E and PAS stainings. Sperm chromatin condensation and relative expression of c-kit and prm 1 genes were assessed by aniline blue staining and real-time PCR, respectively. The mean number of spermatogenic cells, Leydig, Myoid, Sertoli, spermatogenesis parameters, Johnson score, as well as germinal epithelial height and diameters of seminiferous tubules decreased significantly after I/R injury. The thickness of basement membrane and percentage of sperm with excessive histone significantly increased, while the relative expression of c-kit and prm 1 significantly decreased in torsion detorsion group (p<0.001). hAMSCs secreted factors remarkably restored normal sperm chromatin condensation, spermatogenesis parameters and histomorphometric organization of seminiferous tubules via intratesticular injection (p<0.001). Thus, hAMSCs secreted factors may potentially salvage torsion-detorsion-induced infertility.
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Affiliation(s)
- Farnaz Khadivi
- Department of Anatomy, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran.
| | - Sina Mojaverrostami
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahya Ramesh
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Tayebeh Rastegar
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Yasaman Abbasi
- School of dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Bashiri
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Omid fertility and infertility clinic, Hamedan, Iran
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25
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Abrishamdar M, Jalali MS, Yazdanfar N. The role of exosomes in pathogenesis and the therapeutic efficacy of mesenchymal stem cell-derived exosomes against Parkinson's disease. Neurol Sci 2023:10.1007/s10072-023-06706-y. [PMID: 36949298 DOI: 10.1007/s10072-023-06706-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 02/21/2023] [Indexed: 03/24/2023]
Abstract
Parkinson's disease (PD) is a chronic, progressive, neurodegenerative disease. The predominant pathology of PD is the loss of dopaminergic cells in the substantia nigra. Cell transplantation is a strategy with significant potential for treating PD; mesenchymal stem cells (MSCs) are a tremendous therapeutic cell source because they are easily accessible. MSC-derived exosomes with potential protective action in lesioned sites serve as an essential promoter of neuroprotection, and neurodifferentiation, by modulating neural stem cells, neurons, glial cells, and axonal growth in vitro and in vivo environments. The biological properties of MSC-derived exosomes have been proposed as a beneficial tool in different pathological conditions, including PD. Therefore, in this review, we assort the current understanding of MSC-derived exosomes as a new possible therapeutic strategy for PD by providing an overview of the potential role of miRNAs as a component of exosomes in the cellular and molecular basis of PD.
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Affiliation(s)
- Maryam Abrishamdar
- Department of Physiology, Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Maryam Sadat Jalali
- Department of Physiology, Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Neda Yazdanfar
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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26
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Ciccocioppo R, Guadalajara H, Astori G, Carlino G, García-Olmo D. Misconceptions, hurdles and recommendations regarding the use of mesenchymal stem/stromal cells in perianal Crohn disease. Cytotherapy 2023; 25:230-234. [PMID: 36543715 DOI: 10.1016/j.jcyt.2022.11.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 10/14/2022] [Accepted: 11/26/2022] [Indexed: 12/24/2022]
Affiliation(s)
- Rachele Ciccocioppo
- Gastroenterology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata Policlinico G.B. Rossi and University of Verona, Verona, Italy.
| | - Hector Guadalajara
- Division of Surgery and Cell Therapy Unit, Institute for Health Research, Jiménez Díaz Foundation University Hospital, Madrid, Spain
| | - Giuseppe Astori
- Laboratory of Advanced Cellular Therapies, Hematology Unit, Vicenza Hospital, Vicenza, Italy
| | - Giorgio Carlino
- Gastroenterology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata Policlinico G.B. Rossi and University of Verona, Verona, Italy
| | - Damián García-Olmo
- Division of Surgery and Cell Therapy Unit, Institute for Health Research, Jiménez Díaz Foundation University Hospital, Madrid, Spain
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27
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Breast Cancer Exosomal microRNAs Facilitate Pre-Metastatic Niche Formation in the Bone: A Mathematical Model. Bull Math Biol 2023; 85:12. [PMID: 36607440 DOI: 10.1007/s11538-022-01117-0] [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: 08/29/2022] [Accepted: 12/26/2022] [Indexed: 01/07/2023]
Abstract
Pre-metastatic niche is a location where cancer cells, separating from a primary tumor, find "fertile soil" for growth and proliferation, ensuring successful metastasis. Exosomal miRNAs of breast cancer are known to enter the bone and degrade it, which facilitates cancer cells invasion into the bone interior and ensures its successful colonization. In this paper, we use a mathematical model to first describe, in health, the continuous remodeling of the bone by bone-forming osteoblasts, bone-resorbing osteoclasts and the RANKL-OPG-RANK signaling system, which keeps the balance between bone formation and bone resorption. We next demonstrate how breast cancer exosomal miRNAs disrupt this balance, either by increasing or by decreasing the ratio of osteoclasts/osteoblasts, which results in abnormal high bone resorption or abnormal high bone forming, respectively, and in bone weakening in both cases. Finally we consider the case of abnormally high resorption and evaluate the effect of drugs, which may increase bone density to normal level, thus protecting the bone from invasion by cancer cells.
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28
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Anwar I, Ashfaq UA. Impact of Nanotechnology on Differentiation and Augmentation of Stem Cells for Liver Therapy. Crit Rev Ther Drug Carrier Syst 2023; 40:89-116. [PMID: 37585310 DOI: 10.1615/critrevtherdrugcarriersyst.2023042400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/18/2023]
Abstract
The liver is one of the crucial organs of the body that performs hundreds of chemical reactions needed by the body to survive. It is also the largest gland of the body. The liver has multiple functions, including the synthesis of chemicals, metabolism of nutrients, and removal of toxins. It also acts as a storage unit. The liver has a unique ability to regenerate itself, but it can lead to permanent damage if the injury is beyond recovery. The only possible treatment of severe liver damage is liver transplant which is a costly procedure and has several other drawbacks. Therefore, attention has been shifted towards the use of stem cells that have shown the ability to differentiate into hepatocytes. Among the numerous kinds of stem cells (SCs), the mesenchymal stem cells (MSCs) are the most famous. Various studies suggest that an MSC transplant can repair liver function, improve the signs and symptoms, and increase the chances of survival. This review discusses the impact of combining stem cell therapy with nanotechnology. By integrating stem cell science and nanotechnology, the information about stem cell differentiation and regulation will increase, resulting in a better comprehension of stem cell-based treatment strategies. The augmentation of SCs with nanoparticles has been shown to boost the effect of stem cell-based therapy. Also, the function of green nanoparticles in liver therapies is discussed.
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Affiliation(s)
- Ifrah Anwar
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
| | - Usman Ali Ashfaq
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, Pakistan
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29
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Hypothermic Preservation of Adipose-Derived Mesenchymal Stromal Cells as a Viable Solution for the Storage and Distribution of Cell Therapy Products. BIOENGINEERING (BASEL, SWITZERLAND) 2022; 9:bioengineering9120805. [PMID: 36551011 PMCID: PMC9774331 DOI: 10.3390/bioengineering9120805] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/01/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022]
Abstract
Cell and gene therapies (CGT) have reached new therapeutic targets but have noticeably high prices. Solutions to reduce production costs might be found in CGT storage and transportation since they typically involve cryopreservation, which is a heavily burdened process. Encapsulation at hypothermic temperatures (e.g., 2-8 °C) could be a feasible alternative. Adipose tissue-derived mesenchymal stromal cells (MSC(AT)) expanded using fetal bovine serum (FBS)- (MSC-FBS) or human platelet lysate (HPL)-supplemented mediums (MSC-HPL) were encapsulated in alginate beads for 30 min, 5 days, and 12 days. After bead release, cell recovery and viability were determined to assess encapsulation performance. MSC identity was verified by flow cytometry, and a set of assays was performed to evaluate functionality. MSC(AT) were able to survive encapsulated for a standard transportation period of 5 days, with recovery values of 56 ± 5% for MSC-FBS and 77 ± 6% for MSC-HPL (which is a negligible drop compared to earlier timepoints). Importantly, MSC function did not suffer from encapsulation, with recovered cells showing robust differentiation potential, expression of immunomodulatory molecules, and hematopoietic support capacity. MSC(AT) encapsulation was proven possible for a remarkable 12 day period. There is currently no solution to completely replace cryopreservation in CGT logistics and supply chain, although encapsulation has shown potential to act as a serious competitor.
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30
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Liu M, Liu X, Su Y, Li S, Chen Y, Liu A, Guo J, Xuan K, Qiu X. Emerging role of mesenchymal stem cell-derived extracellular vesicles in oral and craniomaxillofacial tissue regenerative medicine. Front Bioeng Biotechnol 2022; 10:1054370. [PMID: 36524049 PMCID: PMC9744765 DOI: 10.3389/fbioe.2022.1054370] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 11/03/2022] [Indexed: 06/11/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells with differentiation potential and paracrine properties, drawing significant attention in the field of regenerative medicine. Extracellular vesicles (EVs), mainly including exosomes, microvesicles and apoptotic bodies (ABs), are predominantly endosomal in origin and contain bioactive molecules, such as miRNAs, mRNAs, and proteins, which are transferred from their original cells to target cells. Recently it has emerged that MSC-derived EVs (MSC-EVs) combine the advantages of MSCs and EVs, which may be used as a promising MSC-based therapy in tissue repair and regeneration. Oral and craniomaxillofacial diseases are clinically complications containing the soft and hard tissues in craniofacial and dental arches. These diseases are often induced by various factors, such as chemical, microbiological, physical factors, and systemic disorders. For decades, tissue repair and regeneration in oral and craniomaxillofacial regions provide substantial improvements in the prevention and treatment of some severe diseases. In this review we discuss MSC-EVs and their therapeutic potential in oral and craniomaxillofacial tissue regenerative medicine.
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Affiliation(s)
- Meng Liu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Department of Preventive Dentistry, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Xin Liu
- Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Yuting Su
- Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Shijie Li
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Department of Preventive Dentistry, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Yuan Chen
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Department of Preventive Dentistry, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Anqi Liu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Department of Preventive Dentistry, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Jing Guo
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Department of Preventive Dentistry, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Kun Xuan
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Department of Preventive Dentistry, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Xinyu Qiu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Department of Preventive Dentistry, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, China
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Pichardo AH, Amadeo F, Wilm B, Lévy R, Ressel L, Murray P, Sée V. Optical Tissue Clearing to Study the Intra-Pulmonary Biodistribution of Intravenously Delivered Mesenchymal Stromal Cells and Their Interactions with Host Lung Cells. Int J Mol Sci 2022; 23:14171. [PMID: 36430651 PMCID: PMC9699424 DOI: 10.3390/ijms232214171] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 11/06/2022] [Accepted: 11/08/2022] [Indexed: 11/18/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) injected intravenously are trapped in the capillaries of the lungs and die within the first 24 h. Studying the biodistribution and fate of labelled therapeutic cells in the 3D pulmonary context is important to understand their function in this organ and gain insights into their mechanisms of action. Optical tissue clearing enables volumetric cell tracking at single-cell resolution. Thus, we compared three optical tissue-clearing protocols (Clear, Unobstructed Brain/Body Imaging Cocktails and Computational analysis (CUBIC), modified stabilised 3D imaging of solvent-cleared organs (s-DISCO) and ethyl cinnamate (ECi)) to evaluate their potential to track the biodistribution of human umbilical cord MSCs expressing the tdTomato fluorescence reporter and investigate how they interact with host cells in the mouse lung. The results showed that although CUBIC clearing is the only method that enables direct imaging of fluorescently labelled MSCs, combining s-DISCO or ECi with immunofluorescence or dye labelling allows the interaction of MSCs with endothelial and immune cells to be studied. Overall, this comparative study offers guidance on selecting an optical tissue-clearing method for cell tracking applications.
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Affiliation(s)
- Alejandra Hernandez Pichardo
- Department of Molecular Physiology and Cell Signalling, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 3BX, UK
- Centre for Preclinical Imaging, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 3BX, UK
| | - Francesco Amadeo
- Department of Molecular Physiology and Cell Signalling, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 3BX, UK
- Centre for Preclinical Imaging, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 3BX, UK
| | - Bettina Wilm
- Department of Molecular Physiology and Cell Signalling, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 3BX, UK
- Centre for Preclinical Imaging, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 3BX, UK
| | - Raphaël Lévy
- INSERM, LVTS, Université Sorbonne Paris Nord, F-75018 Paris, France
| | - Lorenzo Ressel
- Department of Veterinary Anatomy Physiology and Pathology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 3BX, UK
| | - Patricia Murray
- Department of Molecular Physiology and Cell Signalling, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 3BX, UK
- Centre for Preclinical Imaging, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 3BX, UK
| | - Violaine Sée
- CNRS UMR 5305, Tissue Biology and Therapeutic Engineering Laboratory (LBTI), University Claude Bernard Lyon1, 69007 Lyon, France
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Clinical Application of Induced Hepatocyte-like Cells Produced from Mesenchymal Stromal Cells: A Literature Review. Cells 2022; 11:cells11131998. [PMID: 35805080 PMCID: PMC9265349 DOI: 10.3390/cells11131998] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/15/2022] [Accepted: 06/16/2022] [Indexed: 11/17/2022] Open
Abstract
Liver disease is a leading cause of mortality worldwide, resulting in 1.3 million deaths annually. The vast majority of liver disease is caused by metabolic disease (i.e., NASH) and alcohol-induced hepatitis, and to a lesser extent by acute and chronic viral infection. Furthermore, multiple insults to the liver is becoming common due to the prevalence of metabolic and alcohol-related liver diseases. Despite this rising prevalence of liver disease, there are few treatment options: there are treatments for viral hepatitis C and there is vaccination for hepatitis B. Aside from the management of metabolic syndrome, no direct liver therapy has shown clinical efficacy for metabolic liver disease, there is very little for acute alcohol-induced liver disease, and liver transplantation remains the only effective treatment for late-stage liver disease. Traditional pharmacologic interventions have failed to appreciably impact the pathophysiology of alcohol-related liver disease or end-stage liver disease. The difficulties associated with developing liver-specific therapies result from three factors that are common to late-stage liver disease arising from any cause: hepatocyte injury, inflammation, and aberrant tissue healing. Hepatocyte injury results in tissue damage with inflammation, which sensitizes the liver to additional hepatocyte injury and stimulates hepatic stellate cells and aberrant tissue healing responses. In the setting of chronic liver insults, there is progressive scarring, the loss of hepatocyte function, and hemodynamic dysregulation. Regenerative strategies using hepatocyte-like cells that are manufactured from mesenchymal stromal cells may be able to correct this pathophysiology through multiple mechanisms of action. Preclinical studies support their effectiveness and recent clinical studies suggest that cell replacement therapy can be safe and effective in patients with liver disease for whom there is no other option.
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Fernández-Santos ME, Garcia-Arranz M, Andreu EJ, García-Hernández AM, López-Parra M, Villarón E, Sepúlveda P, Fernández-Avilés F, García-Olmo D, Prosper F, Sánchez-Guijo F, Moraleda JM, Zapata AG. Optimization of Mesenchymal Stromal Cell (MSC) Manufacturing Processes for a Better Therapeutic Outcome. Front Immunol 2022; 13:918565. [PMID: 35812460 PMCID: PMC9261977 DOI: 10.3389/fimmu.2022.918565] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 05/10/2022] [Indexed: 12/20/2022] Open
Abstract
MSCs products as well as their derived extracellular vesicles, are currently being explored as advanced biologics in cell-based therapies with high expectations for their clinical use in the next few years. In recent years, various strategies designed for improving the therapeutic potential of mesenchymal stromal cells (MSCs), including pre-conditioning for enhanced cytokine production, improved cell homing and strengthening of immunomodulatory properties, have been developed but the manufacture and handling of these cells for their use as advanced therapy medicinal products (ATMPs) remains insufficiently studied, and available data are mainly related to non-industrial processes. In the present article, we will review this topic, analyzing current information on the specific regulations, the selection of living donors as well as MSCs from different sources (bone marrow, adipose tissue, umbilical cord, etc.), in-process quality controls for ensuring cell efficiency and safety during all stages of the manual and automatic (bioreactors) manufacturing process, including cryopreservation, the use of cell banks, handling medicines, transport systems of ATMPs, among other related aspects, according to European and US legislation. Our aim is to provide a guide for a better, homogeneous manufacturing of therapeutic cellular products with special reference to MSCs.
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Affiliation(s)
- Maria Eugenia Fernández-Santos
- Cardiology Department, HGU Gregorio Marañón. GMP-ATMPs Production Unit, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM). Complutense University, CIBER Cardiovascular (CIBERCV), ISCIII, Madrid, Spain
- Platform GMP Units from TerCel and TERAV Networks. RETIC TerCel & RICORS TERAV, ISCIII, Madrid, Spain
| | - Mariano Garcia-Arranz
- Platform GMP Units from TerCel and TERAV Networks. RETIC TerCel & RICORS TERAV, ISCIII, Madrid, Spain
- New Therapies Laboratory, Health Research Institute-Fundación Jiménez Díaz University Hospital (IIS-FJD). Surgery Department, Autonoma University of Madrid, Madrid, Spain
| | - Enrique J. Andreu
- Platform GMP Units from TerCel and TERAV Networks. RETIC TerCel & RICORS TERAV, ISCIII, Madrid, Spain
- Hematology Department and Cell Therapy Area, Clínica Universidad de Navarra. CIBEROC and IDISNA, Pamplona, Spain
| | - Ana Maria García-Hernández
- Platform GMP Units from TerCel and TERAV Networks. RETIC TerCel & RICORS TERAV, ISCIII, Madrid, Spain
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, Virgen de la Arrixaca University Hospital, University of Murcia, Murcia, Spain
| | - Miriam López-Parra
- Platform GMP Units from TerCel and TERAV Networks. RETIC TerCel & RICORS TERAV, ISCIII, Madrid, Spain
- Cell Therapy Area and Hematology Department, IBSAL-University Hospital of Salamanca, University of Salamanca, Salamanca, Spain
| | - Eva Villarón
- Platform GMP Units from TerCel and TERAV Networks. RETIC TerCel & RICORS TERAV, ISCIII, Madrid, Spain
- Cell Therapy Area and Hematology Department, IBSAL-University Hospital of Salamanca, University of Salamanca, Salamanca, Spain
| | - Pilar Sepúlveda
- Platform GMP Units from TerCel and TERAV Networks. RETIC TerCel & RICORS TERAV, ISCIII, Madrid, Spain
- Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - Francisco Fernández-Avilés
- Cardiology Department, HGU Gregorio Marañón. GMP-ATMPs Production Unit, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM). Complutense University, CIBER Cardiovascular (CIBERCV), ISCIII, Madrid, Spain
- Platform GMP Units from TerCel and TERAV Networks. RETIC TerCel & RICORS TERAV, ISCIII, Madrid, Spain
| | - Damian García-Olmo
- Platform GMP Units from TerCel and TERAV Networks. RETIC TerCel & RICORS TERAV, ISCIII, Madrid, Spain
- New Therapies Laboratory, Health Research Institute-Fundación Jiménez Díaz University Hospital (IIS-FJD). Surgery Department, Autonoma University of Madrid, Madrid, Spain
| | - Felipe Prosper
- Platform GMP Units from TerCel and TERAV Networks. RETIC TerCel & RICORS TERAV, ISCIII, Madrid, Spain
- Hematology Department and Cell Therapy Area, Clínica Universidad de Navarra. CIBEROC and IDISNA, Pamplona, Spain
| | - Fermin Sánchez-Guijo
- Platform GMP Units from TerCel and TERAV Networks. RETIC TerCel & RICORS TERAV, ISCIII, Madrid, Spain
- Cell Therapy Area and Hematology Department, IBSAL-University Hospital of Salamanca, University of Salamanca, Salamanca, Spain
| | - Jose M. Moraleda
- Platform GMP Units from TerCel and TERAV Networks. RETIC TerCel & RICORS TERAV, ISCIII, Madrid, Spain
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, Virgen de la Arrixaca University Hospital, University of Murcia, Murcia, Spain
| | - Agustin G. Zapata
- Platform GMP Units from TerCel and TERAV Networks. RETIC TerCel & RICORS TERAV, ISCIII, Madrid, Spain
- Department of Cell Biology, Complutense University, Madrid, Spain
- *Correspondence: Maria Eugenia Fernández-Santos, ; Agustin G. Zapata,
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Impact of Cryopreservation and Freeze-Thawing on Therapeutic Properties of Mesenchymal Stromal/Stem Cells and Other Common Cellular Therapeutics. CURRENT STEM CELL REPORTS 2022; 8:72-92. [PMID: 35502223 PMCID: PMC9045030 DOI: 10.1007/s40778-022-00212-1] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/28/2022] [Indexed: 12/19/2022]
Abstract
Purpose of Review Cryopreservation and its associated freezing and thawing procedures–short “freeze-thawing”–are among the final steps in economically viable manufacturing and clinical application of diverse cellular therapeutics. Translation from preclinical proof-of-concept studies to larger clinical trials has indicated that these processes may potentially present an Achilles heel to optimal cell product safety and particularly efficacy in clinical trials and routine use. Recent Findings We review the current state of the literature on how cryopreservation of cellular therapies has evolved and how the application of this technique to different cell types is interlinked with their ability to engraft and function upon transfer in vivo, in particular for hematopoietic stem and progenitor cells (HSPCs), their progeny, and therapeutic cell products derived thereof. We also discuss pros and cons how this may differ for non-hematopoietic mesenchymal stromal/stem cell (MSC) therapeutics. We present different avenues that may be crucial for cell therapy optimization, both, for hematopoietic (e.g., effector, regulatory, and chimeric antigen receptor (CAR)-modified T and NK cell based products) and for non-hematopoietic products, such as MSCs and induced pluripotent stem cells (iPSCs), to achieve optimal viability, recovery, effective cell dose, and functionality of the cryorecovered cells. Summary Targeted research into optimizing the cryopreservation and freeze-thawing routines and the adjunct manufacturing process design may provide crucial advantages to increase both the safety and efficacy of cellular therapeutics in clinical use and to enable effective market deployment strategies to become economically viable and sustainable medicines.
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Mönch D, Reinders MEJ, Dahlke MH, Hoogduijn MJ. How to Make Sense out of 75,000 Mesenchymal Stromal Cell Publications? Cells 2022; 11:cells11091419. [PMID: 35563725 PMCID: PMC9101744 DOI: 10.3390/cells11091419] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/20/2022] [Accepted: 04/21/2022] [Indexed: 02/01/2023] Open
Abstract
Mesenchymal stromal cells have been the subject of an expanding number of studies over the past decades. Today, over 75,000 publications are available that shine light on the biological properties and therapeutic effects of these versatile cells in numerous pre-clinical models and early-phase clinical trials. The massive number of papers makes it hard for researchers to comprehend the whole field, and furthermore, they give the impression that mesenchymal stromal cells are wonder cells that are curative for any condition. It is becoming increasingly difficult to dissect how and for what conditions mesenchymal stromal cells exhibit true and reproducible therapeutic effects. This article tries to address the question how to make sense of 75,000, and still counting, publications on mesenchymal stromal cells.
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Affiliation(s)
- Dina Mönch
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany;
- University of Tübingen, 72074 Tübingen, Germany
| | - Marlies E. J. Reinders
- Erasmus MC Transplant Institute, Department of Internal Medicine, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands;
| | - Marc H. Dahlke
- Department of Surgery, Robert-Bosch-Hospital, 70376 Stuttgart, Germany;
| | - Martin J. Hoogduijn
- Erasmus MC Transplant Institute, Department of Internal Medicine, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands;
- Correspondence:
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Heras KL, Igartua M, Santos-Vizcaino E, Hernandez RM. Cell-based dressings: A journey through chronic wound management. BIOMATERIALS ADVANCES 2022; 135:212738. [PMID: 35929212 DOI: 10.1016/j.bioadv.2022.212738] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 02/22/2022] [Accepted: 02/25/2022] [Indexed: 06/15/2023]
Abstract
The field of regenerative medicine has undergone a paradigm shift in recent decades thanks to the emergence of novel therapies based on the use of living organisms. The development of cell-based strategies has become a trend for the treatment of different conditions and pathologies. In this sense, the need for more adequate, biomimetic and well-planned treatments for chronic wounds has found different and innovative strategies, based on the combination of cells with dressings, which seek to revolutionize the wound healing management. Therefore, the objective of this review is to analyze the current state and the latest advances in the research of cell-based dressings for chronic wounds, ranging from traditional and "second generation" bioengineered living skin equivalents to mesenchymal stem cell dressings; the latter include biopolymeric porous scaffolds, electrospun nanofiber meshes, hydrogels and 3D printed bio-printed dressings. Finally, this review updates the completed and ongoing clinical trials in this field and encourages researchers to rethink these new approaches, manufacturing processes and mechanisms of action, as well as their administration strategies and timings.
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Affiliation(s)
- Kevin Las Heras
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain
| | - Manoli Igartua
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 01006 Vitoria-Gasteiz, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain
| | - Edorta Santos-Vizcaino
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 01006 Vitoria-Gasteiz, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain.
| | - Rosa Maria Hernandez
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 01006 Vitoria-Gasteiz, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain.
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Brachtl G, Poupardin R, Hochmann S, Raninger A, Jürchott K, Streitz M, Schlickeiser S, Oeller M, Wolf M, Schallmoser K, Volk HD, Geissler S, Strunk D. Batch Effects during Human Bone Marrow Stromal Cell Propagation Prevail Donor Variation and Culture Duration: Impact on Genotype, Phenotype and Function. Cells 2022; 11:946. [PMID: 35326396 PMCID: PMC8946746 DOI: 10.3390/cells11060946] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 03/04/2022] [Accepted: 03/08/2022] [Indexed: 02/01/2023] Open
Abstract
Donor variation is a prominent critical issue limiting the applicability of cell-based therapies. We hypothesized that batch effects during propagation of bone marrow stromal cells (BMSCs) in human platelet lysate (hPL), replacing fetal bovine serum (FBS), can affect phenotypic and functional variability. We therefore investigated the impact of donor variation, hPL- vs. FBS-driven propagation and exhaustive proliferation, on BMSC epigenome, transcriptome, phenotype, coagulation risk and osteochondral regenerative function. Notably, propagation in hPL significantly increased BMSC proliferation, created significantly different gene expression trajectories and distinct surface marker signatures, already after just one passage. We confirmed significantly declining proliferative potential in FBS-expanded BMSC after proliferative challenge. Flow cytometry verified the canonical fibroblastic phenotype in culture-expanded BMSCs. We observed limited effects on DNA methylation, preferentially in FBS-driven cultures, irrespective of culture duration. The clotting risk increased over culture time. Moreover, expansion in xenogenic serum resulted in significant loss of function during 3D cartilage disk formation and significantly increased clotting risk. Superior chondrogenic function under hPL-conditions was maintained over culture. The platelet blood group and isoagglutinins had minor impact on BMSC function. These data demonstrate pronounced batch effects on BMSC transcriptome, phenotype and function due to serum factors, partly outcompeting donor variation after just one culture passage.
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Affiliation(s)
- Gabriele Brachtl
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Cell Therapy Institute, Paracelsus Medical University (PMU), 5020 Salzburg, Austria; (G.B.); (R.P.); (S.H.); (A.R.); (M.W.)
| | - Rodolphe Poupardin
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Cell Therapy Institute, Paracelsus Medical University (PMU), 5020 Salzburg, Austria; (G.B.); (R.P.); (S.H.); (A.R.); (M.W.)
| | - Sarah Hochmann
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Cell Therapy Institute, Paracelsus Medical University (PMU), 5020 Salzburg, Austria; (G.B.); (R.P.); (S.H.); (A.R.); (M.W.)
| | - Anna Raninger
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Cell Therapy Institute, Paracelsus Medical University (PMU), 5020 Salzburg, Austria; (G.B.); (R.P.); (S.H.); (A.R.); (M.W.)
| | - Karsten Jürchott
- Center for Regenerative Therapies (BCRT), Berlin Institute of Health (BIH), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; (K.J.); (M.S.); (S.S.); (H.-D.V.); (S.G.)
| | - Mathias Streitz
- Center for Regenerative Therapies (BCRT), Berlin Institute of Health (BIH), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; (K.J.); (M.S.); (S.S.); (H.-D.V.); (S.G.)
- Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Insel Riems, 17493 Greifswald, Germany
| | - Stephan Schlickeiser
- Center for Regenerative Therapies (BCRT), Berlin Institute of Health (BIH), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; (K.J.); (M.S.); (S.S.); (H.-D.V.); (S.G.)
| | - Michaela Oeller
- Department of Transfusion Medicine and SCI-TReCS, Paracelsus Medical University (PMU), 5020 Salzburg, Austria; (M.O.); (K.S.)
| | - Martin Wolf
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Cell Therapy Institute, Paracelsus Medical University (PMU), 5020 Salzburg, Austria; (G.B.); (R.P.); (S.H.); (A.R.); (M.W.)
| | - Katharina Schallmoser
- Department of Transfusion Medicine and SCI-TReCS, Paracelsus Medical University (PMU), 5020 Salzburg, Austria; (M.O.); (K.S.)
| | - Hans-Dieter Volk
- Center for Regenerative Therapies (BCRT), Berlin Institute of Health (BIH), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; (K.J.); (M.S.); (S.S.); (H.-D.V.); (S.G.)
- Berlin Center for Advanced Therapies (BeCAT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany
- Institute of Medical Immunology, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Sven Geissler
- Center for Regenerative Therapies (BCRT), Berlin Institute of Health (BIH), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; (K.J.); (M.S.); (S.S.); (H.-D.V.); (S.G.)
- Berlin Center for Advanced Therapies (BeCAT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Dirk Strunk
- Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Cell Therapy Institute, Paracelsus Medical University (PMU), 5020 Salzburg, Austria; (G.B.); (R.P.); (S.H.); (A.R.); (M.W.)
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The osteoprotective role of USP26 in coordinating bone formation and resorption. Cell Death Differ 2022; 29:1123-1136. [PMID: 35091692 PMCID: PMC9177963 DOI: 10.1038/s41418-021-00904-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 11/12/2021] [Accepted: 11/12/2021] [Indexed: 12/15/2022] Open
Abstract
Bone homeostasis is maintained through a balance of bone formation by osteoblasts and bone resorption by osteoclasts. Ubiquitin-specific proteases (USPs) are involved in regulating bone metabolism by preserving bone formation or antagonizing bone resorption. However, the specific USPs that maintain bone homeostasis by orchestrating bone formation and bone resorption simultaneously are poorly understood. Here, we identified USP26 as a previously unknown regulator of bone homeostasis that coordinates bone formation and resorption. Mechanistically, USP26 stabilizes β-catenin to promote the osteogenic activity of mesenchymal cells (MSCs) and impairs the osteoclastic differentiation of bone myelomonocytes (BMMs) by stabilizing inhibitors of NF-κBα (IκBα). Gain-of-function experiments revealed that Usp26 supplementation significantly increased bone regeneration in bone defects in aged mice and decreased bone loss resulting from ovariectomy. Taken together, these data show the osteoprotective effect of USP26 via the coordination of bone formation and resorption, suggesting that USP26 represents a potential therapeutic target for osteoporosis.
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Najar M, Melki R, Khalife F, Lagneaux L, Bouhtit F, Moussa Agha D, Fahmi H, Lewalle P, Fayyad-Kazan M, Merimi M. Therapeutic Mesenchymal Stem/Stromal Cells: Value, Challenges and Optimization. Front Cell Dev Biol 2022; 9:716853. [PMID: 35096805 PMCID: PMC8795900 DOI: 10.3389/fcell.2021.716853] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 11/02/2021] [Indexed: 12/13/2022] Open
Abstract
Cellular therapy aims to replace damaged resident cells by restoring cellular and molecular environments suitable for tissue repair and regeneration. Among several candidates, mesenchymal stem/stromal cells (MSCs) represent a critical component of stromal niches known to be involved in tissue homeostasis. In vitro, MSCs appear as fibroblast-like plastic adherent cells regardless of the tissue source. The therapeutic value of MSCs is being explored in several conditions, including immunological, inflammatory and degenerative diseases, as well as cancer. An improved understanding of their origin and function would facilitate their clinical use. The stemness of MSCs is still debated and requires further study. Several terms have been used to designate MSCs, although consensual nomenclature has yet to be determined. The presence of distinct markers may facilitate the identification and isolation of specific subpopulations of MSCs. Regarding their therapeutic properties, the mechanisms underlying their immune and trophic effects imply the secretion of various mediators rather than direct cellular contact. These mediators can be packaged in extracellular vesicles, thus paving the way to exploit therapeutic cell-free products derived from MSCs. Of importance, the function of MSCs and their secretome are significantly sensitive to their environment. Several features, such as culture conditions, delivery method, therapeutic dose and the immunobiology of MSCs, may influence their clinical outcomes. In this review, we will summarize recent findings related to MSC properties. We will also discuss the main preclinical and clinical challenges that may influence the therapeutic value of MSCs and discuss some optimization strategies.
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Affiliation(s)
- Mehdi Najar
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
| | - Rahma Melki
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Ferial Khalife
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Hadath, Lebanon
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Fatima Bouhtit
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Douaa Moussa Agha
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Hassan Fahmi
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
| | - Philippe Lewalle
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
| | - Mohammad Fayyad-Kazan
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Hadath, Lebanon
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Hadath, Lebanon
| | - Makram Merimi
- Genetics and Immune-Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
- Laboratory of Experimental Hematology, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
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40
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Gonzalez-Pujana A, Beloqui A, Javier Aguirre J, Igartua M, Santos-Vizcaino E, Maria Hernandez R. Mesenchymal stromal cells encapsulated in licensing hydrogels exert delocalized systemic protection against ulcerative colitis via subcutaneous xenotransplantation. Eur J Pharm Biopharm 2022; 172:31-40. [DOI: 10.1016/j.ejpb.2022.01.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 01/14/2022] [Accepted: 01/18/2022] [Indexed: 12/16/2022]
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41
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Potapnev MP. Analysis of approaches to increase the efficacy of cell therapy based on mesenchymal stromal cells. GENES & CELLS 2021; 16:22-28. [DOI: 10.23868/202112003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The review considers the main stages of isolating, processing and clinical use of human mesenchymal stromal cells (MSCs). They included: donor selection, selection of the source of MSCs, methods of isolation of cellular suspension from tissue, culturing in vitro for cell biomass propagation, priming of the resulting cell product, timing and ways of its clinical application, selection of the recipient of MSCs. The analysis of the stages of MSCs preparation and conditions for their use was carried out from the position of the influence on the final therapeutic effect of cell therapy in patients (or experimental animals - in preclinical studies). The optimal parameters of work with MSCs at each stage, the possibility to improve their quality / biological activity in order to increase their therapeutic efficacy were determined. The analysis and ways of avoiding the influence of adverse factors associated with the manufacturing and use of MSCs on the effectiveness of cell therapy in patients were given.
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Lu CH, Chen YA, Ke CC, Liu RS. Mesenchymal Stem Cell-Derived Extracellular Vesicle: A Promising Alternative Therapy for Osteoporosis. Int J Mol Sci 2021; 22:12750. [PMID: 34884554 PMCID: PMC8657894 DOI: 10.3390/ijms222312750] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/15/2021] [Accepted: 11/22/2021] [Indexed: 02/07/2023] Open
Abstract
Osteoporosis is the chronic metabolic bone disease caused by the disturbance of bone remodeling due to the imbalance of osteogenesis and osteoclastogenesis. A large population suffers from osteoporosis, and most of them are postmenopausal women or older people. To date, bisphosphonates are the main therapeutic agents in the treatment of osteoporosis. However, limited therapeutic effects with diverse side effects caused by bisphosphonates hindered the therapeutic applications and decreased the quality of life. Therefore, an alternative therapy for osteoporosis is still needed. Stem cells, especially mesenchymal stem cells, have been shown as a promising medication for numerous human diseases including many refractory diseases. Recently, researchers found that the extracellular vesicles derived from these stem cells possessed the similar therapeutic potential to that of parental cells. To date, a number of studies demonstrated the therapeutic applications of exogenous MSC-EVs for the treatment of osteoporosis. In this article, we reviewed the basic back ground of EVs, the cargo and therapeutic potential of MSC-EVs, and strategies of engineering of MSC-EVs for osteoporosis treatment.
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Affiliation(s)
- Cheng-Hsiu Lu
- Core Laboratory for Phenomics and Diagnostics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan;
- Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Yi-An Chen
- Molecular and Genetic Imaging Core/Taiwan Mouse Clinic, National Comprehensive Mouse Phenotyping and Drug Testing Center, Taipei 112, Taiwan;
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Chien-Chih Ke
- Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Ren-Shyan Liu
- Molecular and Genetic Imaging Core/Taiwan Mouse Clinic, National Comprehensive Mouse Phenotyping and Drug Testing Center, Taipei 112, Taiwan;
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Department of Nuclear Medicine, Cheng Hsin General Hospital, Taipei 112, Taiwan
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- PET Center, Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan
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43
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Munoz-Perez E, Gonzalez-Pujana A, Igartua M, Santos-Vizcaino E, Hernandez RM. Mesenchymal Stromal Cell Secretome for the Treatment of Immune-Mediated Inflammatory Diseases: Latest Trends in Isolation, Content Optimization and Delivery Avenues. Pharmaceutics 2021; 13:pharmaceutics13111802. [PMID: 34834217 PMCID: PMC8617629 DOI: 10.3390/pharmaceutics13111802] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/21/2021] [Accepted: 10/21/2021] [Indexed: 12/11/2022] Open
Abstract
Considering the high prevalence and the complex pharmacological management of immune-mediated inflammatory diseases (IMIDs), the search for new therapeutic approaches for their treatment is vital. Although the immunomodulatory and anti-inflammatory effects of mesenchymal stromal cells (MSCs) have been extensively studied as a potential therapy in this field, direct MSC implantation presents some limitations that could slow down the clinical translation. Since the beneficial effects of MSCs have been mainly attributed to their ability to secrete a plethora of bioactive factors, their secretome has been proposed as a new and promising pathway for the treatment of IMIDs. Formed from soluble factors and extracellular vesicles (EVs), the MSC-derived secretome has been proven to elicit immunomodulatory effects that control the inflammatory processes that occur in IMIDs. This article aims to review the available knowledge on the MSC secretome, evaluating the advances in this field in terms of its composition, production and application, as well as analyzing the pending challenges in the field. Moreover, the latest research involving secretome administration in IMIDs is discussed to provide an updated state-of-the-art for this field. Finally, novel secretome delivery alternatives are reviewed, paying special attention to hydrogel encapsulation as one of the most convenient and promising strategies.
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Affiliation(s)
- Elena Munoz-Perez
- NanoBioCel Research Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (E.M.-P.); (A.G.-P.); (M.I.)
| | - Ainhoa Gonzalez-Pujana
- NanoBioCel Research Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (E.M.-P.); (A.G.-P.); (M.I.)
- Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, 28029 Madrid, Spain
- Bioaraba, NanoBioCel Research Group, 01006 Vitoria-Gasteiz, Spain
| | - Manoli Igartua
- NanoBioCel Research Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (E.M.-P.); (A.G.-P.); (M.I.)
- Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, 28029 Madrid, Spain
- Bioaraba, NanoBioCel Research Group, 01006 Vitoria-Gasteiz, Spain
| | - Edorta Santos-Vizcaino
- NanoBioCel Research Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (E.M.-P.); (A.G.-P.); (M.I.)
- Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, 28029 Madrid, Spain
- Bioaraba, NanoBioCel Research Group, 01006 Vitoria-Gasteiz, Spain
- Correspondence: (E.S.-V.); (R.M.H.)
| | - Rosa Maria Hernandez
- NanoBioCel Research Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (E.M.-P.); (A.G.-P.); (M.I.)
- Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, 28029 Madrid, Spain
- Bioaraba, NanoBioCel Research Group, 01006 Vitoria-Gasteiz, Spain
- Correspondence: (E.S.-V.); (R.M.H.)
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44
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Current Overview on the Use of Mesenchymal Stem Cells for Perianal Fistula Treatment in Patients with Crohn's Disease. Life (Basel) 2021; 11:life11111133. [PMID: 34833009 PMCID: PMC8622588 DOI: 10.3390/life11111133] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 10/12/2021] [Accepted: 10/19/2021] [Indexed: 02/07/2023] Open
Abstract
Perianal fistula in patients with Crohn’s disease is an extremely challenging condition. The disease tends to reoccur, and with current treatment options, a large number of patients are left with active ailment and experience major morbidity. In recent years, hopeful results regarding local use of mesenchymal stem cells (MSCs) in perianal Crohn’s disease have been published. Although to this day there are no clear guidelines determining optimal dosage, injections frequency and culture conditions, their efficiency has proven to be much higher than conventionally used methods. According to studies, they can effectively induce as well as maintain fistula closure. This approach also avoids common side effects related to conventional surgical treatment.
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45
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Krampera M, Le Blanc K. Mesenchymal stromal cells: Putative microenvironmental modulators become cell therapy. Cell Stem Cell 2021; 28:1708-1725. [PMID: 34624232 DOI: 10.1016/j.stem.2021.09.006] [Citation(s) in RCA: 145] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
An exceptional safety profile has been shown in a large number of cell therapy clinical trials that use mesenchymal stromal cells (MSCs). However, reliable potency assays are still lacking to predict MSC immunosuppressive efficacy in the clinical setting. Nevertheless, MSCs are approved in Japan and Europe for the treatment of graft-versus-host and Crohn's fistular diseases, but not in the United States for any clinical indication. We discuss potential mechanisms of action for the therapeutic effects of MSC transplantation, experimental models that dissect tissue modulating function of MSCs, and approaches for identifying MSC effects in vivo by integrating biomarkers of disease and MSC activity.
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Affiliation(s)
- Mauro Krampera
- Section of Hematology and Bone Marrow Transplant Unit, Department of Medicine, University of Verona, Verona, Italy.
| | - Katarina Le Blanc
- Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Stockholm, Sweden; Center of Allogeneic Stem Cell Transplantation and Cellular Therapy (CAST), Karolinska University Hospital, Huddinge, Stockholm, Sweden.
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46
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Strategies to address mesenchymal stem/stromal cell heterogeneity in immunomodulatory profiles to improve cell-based therapies. Acta Biomater 2021; 133:114-125. [PMID: 33857693 DOI: 10.1016/j.actbio.2021.03.069] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 03/15/2021] [Accepted: 03/31/2021] [Indexed: 02/06/2023]
Abstract
Mesenchymal stromal cells (MSCs) have gained immense attention over the past two decades due to their multipotent differentiation potential and pro-regenerative and immunomodulatory cytokine secretory profiles. Their ability to modulate the host immune system and promote tolerance has prompted several allogeneic and autologous hMSC-based clinical trials for the treatment of graft-versus-host disease and several other immune-induced disorders. However, clinical success beyond safety is still controversial and highly variable, with inconclusive therapeutic benefits and little mechanistic explanation. This clinical variability has been broadly attributed to inconsistent MSC sourcing, phenotypic characterization, variable potency, and non-standard isolation protocols, leading to functional heterogeneity among administered MSCs. Homogeneous MSC populations are proposed to yield more predictable, reliable biological responses and clinically meaningful properties relevant to cell-based therapies. Limited comparisons of heterogeneous MSCs with homogenous MSCs are reported. This review addresses this gap in the literature with a critical analysis of strategies aimed at decreasing MSC heterogeneity concerning their reported immunomodulatory profiles. STATEMENT OF SIGNIFICANCE: This review collates, summarizes, and critically analyzes published strategies that seek to improve homogeneity in immunomodulatory functioning MSC populations intended as cell therapies to treat immune-based disorders, such as graft-vs-host-disease. No such review for MSC therapies, immunomodulatory profiles and cell heterogeneity analysis is published. Since MSCs represent the most clinically studied experimental cell therapy platform globally for which there remains no US domestic marketing approval, insights into MSC challenges in therapeutic product development are imperative to providing solutions for immunomodulatory variabilities.
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47
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Swaminathan M, Kopyt N, Atta MG, Radhakrishnan J, Umanath K, Nguyen S, O'Rourke B, Allen A, Vaninov N, Tilles A, LaPointe E, Blair A, Gemmiti C, Miller B, Parekkadan B, Barcia RN. Pharmacological effects of ex vivo mesenchymal stem cell immunotherapy in patients with acute kidney injury and underlying systemic inflammation. Stem Cells Transl Med 2021; 10:1588-1601. [PMID: 34581517 PMCID: PMC8641088 DOI: 10.1002/sctm.21-0043] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 06/07/2021] [Accepted: 06/30/2021] [Indexed: 01/20/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have natural immunoregulatory functions that have been explored for medicinal use as a cell therapy with limited success. A phase Ib study was conducted to evaluate the safety and immunoregulatory mechanism of action of MSCs using a novel ex vivo product (SBI-101) to preserve cell activity in patients with severe acute kidney injury. Pharmacological data demonstrated MSC-secreted factor activity that was associated with anti-inflammatory signatures in the molecular and cellular profiling of patient blood. Systems biology analysis captured multicompartment effects consistent with immune reprogramming and kidney tissue repair. Although the study was not powered for clinical efficacy, these results are supportive of the therapeutic hypothesis, namely, that treatment with SBI-101 elicits an immunotherapeutic response that triggers an accelerated phenotypic switch from tissue injury to tissue repair. Ex vivo administration of MSCs, with increased power of testing, is a potential new biological delivery paradigm that assures sustained MSC activity and immunomodulation.
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Affiliation(s)
- Madhav Swaminathan
- Department of Anesthesiology, Duke University School of Medicine, Duke University, Durham, North Carolina, USA
| | - Nelson Kopyt
- Nephrology Section, Department of Medicine, Lehigh Valley Health Network, Allentown, Pennsylvania, USA
| | - Mohamed G Atta
- Department of Medicine, Division of Nephrology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Jai Radhakrishnan
- Columbia University Medical Center, Division of Nephrology, NY Presbyterian Hospital/Columbia, New York, New York, USA
| | - Kausik Umanath
- Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, Michigan, USA.,Division of Nephrology and Hypertension, Wayne State University, Detroit, Michigan, USA
| | - Sunny Nguyen
- Sentien Biotechnologies, Lexington, Massachusetts, USA
| | | | - Ashley Allen
- Sentien Biotechnologies, Lexington, Massachusetts, USA
| | | | - Arno Tilles
- Sentien Biotechnologies, Lexington, Massachusetts, USA
| | | | - Andrew Blair
- Sentien Biotechnologies, Lexington, Massachusetts, USA
| | - Chris Gemmiti
- Sentien Biotechnologies, Lexington, Massachusetts, USA
| | - Brian Miller
- Sentien Biotechnologies, Lexington, Massachusetts, USA
| | - Biju Parekkadan
- Sentien Biotechnologies, Lexington, Massachusetts, USA.,Department of Surgery, Center for Surgery, Innovation, and Bioengineering, Massachusetts General Hospital, Harvard Medical School and Shriners Hospitals for Children, Boston, Massachusetts, USA.,Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.,Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, USA
| | - Rita N Barcia
- Sentien Biotechnologies, Lexington, Massachusetts, USA
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48
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Gordiienko IM, Gubar OS, Sulik R, Kunakh T, Zlatskiy I, Zlatska A. Empty nose syndrome pathogenesis and cell-based biotechnology products as a new option for treatment. World J Stem Cells 2021; 13:1293-1306. [PMID: 34630863 PMCID: PMC8474723 DOI: 10.4252/wjsc.v13.i9.1293] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/29/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023] Open
Abstract
Empty nose syndrome (ENS) is a rare complication that develops after partial or complete turbinectomy. The main feature of ENS is paradoxical nasal obstruction feeling despite objectively wide nasal airway. ENS pathogenesis is multifactorial and includes changes in laminar physiological airflow, disruption of mucosa functions and deficient neural sensation. This leads to the development of ENS symptomatology such as dyspnea, nasal dryness, nasal burning, nasal obstruction, feeling of suffocation and even comorbid psychiatric disorders that significantly impairs life quality. Specific effective treatment of ENS does not exist up to date. In this review we outline existing biomaterial for surgical reconstitution of nasal anatomy and discuss the perspective of stem cell-based technologies in ENS management. The main focus is directed to justification of rationality application of adult mesenchymal stem cells (MSCs) from different tissues origin and neural crest-derived stem cells (NCSCs) based on their intrinsic biological properties. MSCs transplantation may stimulate mucosa tissue regeneration via trophic factors secretion, direct transdifferentiation into epithelial cells and pronounced immunosuppressive effect. From the other hand, NCSCs based on their high neuroprotective properties may reconstitute nerve structure and functioning leading to normal sensation in ENS patients. We postulate that application of cell-based and tissue-engineered products can help to significantly improve ENS symptomatology only as complex approach aimed at reconstitution of nasal anatomy, recovery the nasal mucosa functionality and neural tissue sensation.
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Affiliation(s)
- Inna M Gordiienko
- Biotechnology Laboratory, Medical Company “Good Cells”, Kyiv 03115, Ukraine
- R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology NAS of Ukraine, Kyiv 03022, Ukraine
| | - Olga S Gubar
- Institute of Molecular Biology and Genetics NAS of Ukraine, Kyiv 03143, Ukraine
| | - Roman Sulik
- Biotechnology Laboratory, Medical Company “Good Cells”, Kyiv 03115, Ukraine
| | - Taras Kunakh
- Biotechnology Laboratory, Medical Company “Good Cells”, Kyiv 03115, Ukraine
| | - Igor Zlatskiy
- State Institute of Genetic and Regenerative Medicine, National Academy of Medical Sciences of Ukraine, Kyiv 04114, Ukraine
| | - Alona Zlatska
- Biotechnology Laboratory, Medical Company “Good Cells”, Kyiv 03115, Ukraine
- State Institute of Genetic and Regenerative Medicine, National Academy of Medical Sciences of Ukraine, Kyiv 04114, Ukraine
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49
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Nguyen MQ, Bui HTH, Tuyet ANT, Nhung TTH, Hoang DM, Liem NT, Hoang VT. Comparative Bioactivity Analysis for Off-the-Shelf and Culture-Rescued Umbilical Cord-Derived Mesenchymal Stem/Stromal Cells in a Xeno- and Serum-Free Culture System. Cell Transplant 2021; 30:9636897211039441. [PMID: 34538123 PMCID: PMC8718162 DOI: 10.1177/09636897211039441] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
We recently reported a standardized xeno- and serum-free culture platform to isolate and expand umbilical cord-derived mesenchymal stem/stromal cells (UC-MSCs). Comparing populations from the same passage, cells that were cryopreserved and culture-rescued exhibited characteristics similar to those of their fresh counterparts, continuously cultured cells without interim cryopreservation. The culture rescue after thawing allowed for the cells to be fully recovered. However, since it would be more cost-effective and timesaving if cryopreserved cells can be used as an off-the-shelf product, we set out to compare the bioactivity of freshly thawed UC-MSCs versus culture-rescued UC-MSCs of the same batch that were recultured for an additional passage under our xeno- and serum-free protocol. UC-MSCs showed high viability in both the freshly thawed and the re-cultured group. Both populations displayed a similar proliferation capacity which is indicated by a comparable population doubling time and colony-forming ability. Both freshly thawed and culture-rescued UC-MSCs expressed the characteristic immunophenotype and were capable of differentiating into osteocytes, chondrocytes, and adipocytes. On the other hand, culture-rescued cells appeared to be more potent in immunosuppression than freshly thawed cells. In conclusion, freshly thawed and culture-rescued cell products share comparable bioactivity in cell growth and proliferation, immunophenotype, and differentiation potential. However, the culture-rescued cells that were allowed to grow for an additional passage appear to display a more favorable immunomodulatory potential when compared to their freshly thawed parent cells.
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Affiliation(s)
- Minh Quang Nguyen
- Vinmec Research Institute of Stem Cell and Gene Technology (VRISG), Vinmec Healthcare System, Hanoi, Vietnam.,VNU University of Science, Vietnam National University, Hanoi, Vietnam
| | - Hue T H Bui
- Vinmec Research Institute of Stem Cell and Gene Technology (VRISG), Vinmec Healthcare System, Hanoi, Vietnam.,Vinmec Institute of Applied Science and Regenerative Medicine (VIASRM), Vinmec Healthcare System, Hanoi, Vietnam
| | - Anh Nguyen Thi Tuyet
- Vinmec Research Institute of Stem Cell and Gene Technology (VRISG), Vinmec Healthcare System, Hanoi, Vietnam.,Vinmec Institute of Applied Science and Regenerative Medicine (VIASRM), Vinmec Healthcare System, Hanoi, Vietnam
| | - Trinh Thi Hong Nhung
- Vinmec Research Institute of Stem Cell and Gene Technology (VRISG), Vinmec Healthcare System, Hanoi, Vietnam.,Vinmec Institute of Applied Science and Regenerative Medicine (VIASRM), Vinmec Healthcare System, Hanoi, Vietnam
| | - Duc M Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology (VRISG), Vinmec Healthcare System, Hanoi, Vietnam
| | - Nguyen Thanh Liem
- Vinmec Research Institute of Stem Cell and Gene Technology (VRISG), Vinmec Healthcare System, Hanoi, Vietnam
| | - Van T Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology (VRISG), Vinmec Healthcare System, Hanoi, Vietnam
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50
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Calcat-i-Cervera S, Sanz-Nogués C, O'Brien T. When Origin Matters: Properties of Mesenchymal Stromal Cells From Different Sources for Clinical Translation in Kidney Disease. Front Med (Lausanne) 2021; 8:728496. [PMID: 34616756 PMCID: PMC8488400 DOI: 10.3389/fmed.2021.728496] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 08/19/2021] [Indexed: 12/14/2022] Open
Abstract
Advanced therapy medicinal products (ATMPs) offer new prospects to improve the treatment of conditions with unmet medical needs. Kidney diseases are a current major health concern with an increasing global prevalence. Chronic renal failure appears after many years of impairment, which opens a temporary window to apply novel therapeutic approaches to delay or halt disease progression. The immunomodulatory, anti-inflammatory, and pro-regenerative properties of mesenchymal stromal cells (MSCs) have sparked interest for their use in cell-based regenerative therapies. Currently, several early-phase clinical trials have been completed and many are ongoing to explore MSC safety and efficacy in a wide range of nephropathies. However, one of the current roadblocks to the clinical translation of MSC therapies relates to the lack of standardization and harmonization of MSC manufacturing protocols, which currently hinders inter-study comparability. Studies have shown that cell culture processing variables can have significant effects on MSC phenotype and functionality, and these are highly variable across laboratories. In addition, heterogeneity within MSC populations is another obstacle. Furthermore, MSCs may be isolated from several sources which adds another variable to the comparative assessment of outcomes. There is now a growing body of literature highlighting unique and distinctive properties of MSCs according to the tissue origin, and that characteristics such as donor, age, sex and underlying medical conditions may alter the therapeutic effect of MSCs. These variables must be taken into consideration when developing a cell therapy product. Having an optimal scale-up strategy for MSC manufacturing is critical for ensuring product quality while minimizing costs and time of production, as well as avoiding potential risks. Ideally, optimal scale-up strategies must be carefully considered and identified during the early stages of development, as making changes later in the bioprocess workflow will require re-optimization and validation, which may have a significant long-term impact on the cost of the therapy. This article provides a summary of important cell culture processing variables to consider in the scale-up of MSC manufacturing as well as giving a comprehensive review of tissue of origin-specific biological characteristics of MSCs and their use in current clinical trials in a range of renal pathologies.
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Affiliation(s)
| | | | - Timothy O'Brien
- Regenerative Medicine Institute (REMEDI), CÚRAM, Biomedical Science Building, National University of Ireland, Galway, Ireland
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