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Gasanov VAO, Kashirskikh DA, Khotina VA, Kuzmina DM, Nikitochkina SY, Mukhina IV, Vorotelyak EA, Vasiliev AV. Preclinical Evaluation of the Safety, Toxicity and Efficacy of Genetically Modified Wharton's Jelly Mesenchymal Stem/Stromal Cells Expressing the Antimicrobial Peptide SE-33. Cells 2025; 14:341. [PMID: 40072070 PMCID: PMC11898551 DOI: 10.3390/cells14050341] [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: 01/14/2025] [Revised: 02/21/2025] [Accepted: 02/24/2025] [Indexed: 03/15/2025] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) offer promising therapeutic potential in cell-based therapies for various diseases. However, the safety of genetically modified MSCs remains poorly understood. This study aimed to evaluate the general toxicity and safety of Wharton's Jelly-Derived MSCs (WJ-MSCs) engineered to express the antimicrobial peptide SE-33 in an animal model. Genetically modified WJ-MSCs expressing SE-33 were administered to C57BL/6 mice at both therapeutic and excessive doses, either once or repeatedly. Animal monitoring included mortality, clinical signs, and behavioral observations. The toxicity assessment involved histopathological, hematological, and biochemical analyses of major organs and tissues, while immunotoxicity and immunogenicity were examined through humoral and cellular immune responses, macrophage phagocytic activity, and lymphocyte blast transformation. Antimicrobial efficacy was evaluated in a Staphylococcus aureus-induced pneumonia model by monitoring animal mortality and assessing bacterial load and inflammatory processes in the lungs. Mice receiving genetically modified WJ-MSCs exhibited no acute or chronic toxicity, behavioral abnormalities, or pathological changes, regardless of the dose or administration frequency. No significant immunotoxicity or alterations in immune responses were observed, and there were no notable changes in hematological or biochemical serum parameters. Infected animals treated with WJ-MSC-SE33 showed a significant reduction in bacterial load and lung inflammation and improved survival compared to control groups, demonstrating efficacy over native WJ-MSCs. Our findings suggest that WJ-MSCs expressing SE-33 are well tolerated, displaying a favorable safety profile comparable to native WJ-MSCs and potent antimicrobial activity, significantly reducing bacterial load, inflammation, and mortality in an S. aureus pneumonia model. These data support the safety profile of WJ-MSCs expressing SE-33 as a promising candidate for cell-based therapies for bacterial infections, particularly those complicated by antibiotic resistance.
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Affiliation(s)
- Vagif Ali oglu Gasanov
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia; (D.A.K.); (E.A.V.)
| | | | - Victoria Alexandrovna Khotina
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia; (D.A.K.); (E.A.V.)
| | - Daria Mikhailovna Kuzmina
- Department of Normal Physiology, Privolzhsky Research Medical University of Ministry of Health of the Russian Federation, Nizhny Novgorod 603005, Russia; (D.M.K.); (I.V.M.)
| | - Sofya Yurievna Nikitochkina
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia; (D.A.K.); (E.A.V.)
| | - Irina Vasilievna Mukhina
- Department of Normal Physiology, Privolzhsky Research Medical University of Ministry of Health of the Russian Federation, Nizhny Novgorod 603005, Russia; (D.M.K.); (I.V.M.)
| | - Ekaterina Andreevna Vorotelyak
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia; (D.A.K.); (E.A.V.)
- Department of Cell Biology, Biological Faculty, Lomonosov Moscow State University, Moscow 119234, Russia
| | - Andrey Valentinovich Vasiliev
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Moscow 119334, Russia; (D.A.K.); (E.A.V.)
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Katano T, Inagaki A, Imura T, Yamana H, Saito R, Endo Kumata Y, Suzuki S, Hagiwara Y, Ohashi K, Watanabe K, Tabata Y, Goto M. A novel approach for hepatocyte transplantation at the liver surface. Cell Transplant 2025; 34:9636897251329308. [PMID: 40208805 DOI: 10.1177/09636897251329308] [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: 04/12/2025] Open
Abstract
Hepatocyte transplantation (HTx) is a promising alternative to liver transplantation; however, poor engraftment remains a major challenge. Although co-transplantation with adipose tissue-derived stromal cells (ADSCs) or islets improves engraftment, exposure of these cells to the portal vein enhances innate immune responses, resulting in a significant loss of hepatocytes. Therefore, we investigated HTx at the liver surface as a novel approach that does not involve the portal vein. Hepatocytes were transplanted onto the liver surface of syngeneic analbuminemic rats with or without ADSCs and/or islets. Serum albumin levels and immunohistochemical staining of the transplanted hepatocytes were evaluated. Hepatocyte engraftment was compared between the liver surface and intraportal groups. To examine the detailed mechanisms behind co-transplantation, co-cultured supernatants were analyzed using multiplex assays, and inhibition tests using neutralizing antibodies were performed. Results showed that islet and ADSC co-transplantation markedly enhanced hepatocyte engraftment at the liver surface (P < 0.01), and its efficiency was comparable to that of intraportal transplantation (P = 0.35). In the co-transplantation group, cells were not necessarily in proximity, suggesting that humoral factors are important. In an in vitro study, hepatocyte function was significantly improved by co-culturing with islets and ADSCs (P < 0.01). Multiplex assays and inhibition tests revealed several important humoral factors, most notably insulin, which promoted hepatocyte engraftment. These findings suggest that HTx at the liver surface, together with crucial factors, may be a novel alternative strategy for intraportal transplantation.
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Affiliation(s)
- Takumi Katano
- Division of Transplantation and Regenerative Medicine, Tohoku University School of Medicine, Sendai, Japan
| | - Akiko Inagaki
- Division of Transplantation and Regenerative Medicine, Tohoku University School of Medicine, Sendai, Japan
| | - Takehiro Imura
- Division of Transplantation and Regenerative Medicine, Tohoku University School of Medicine, Sendai, Japan
| | - Hiroki Yamana
- Department of Surgery, Tohoku University School of Medicine, Sendai, Japan
| | - Ryusuke Saito
- Department of Surgery, Tohoku University School of Medicine, Sendai, Japan
| | - Yukiko Endo Kumata
- Department of Surgery, Tohoku University School of Medicine, Sendai, Japan
| | - Shoki Suzuki
- Department of Surgery, Tohoku University School of Medicine, Sendai, Japan
| | - Yoshiya Hagiwara
- Department of Surgery, Tohoku University School of Medicine, Sendai, Japan
| | - Kazuo Ohashi
- Graduate School and School of Pharmaceutical Sciences, Osaka University, Suita, Japan
| | - Kimiko Watanabe
- Division of Transplantation and Regenerative Medicine, Tohoku University School of Medicine, Sendai, Japan
| | - Yasuhiko Tabata
- Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masafumi Goto
- Division of Transplantation and Regenerative Medicine, Tohoku University School of Medicine, Sendai, Japan
- Department of Surgery, Tohoku University School of Medicine, Sendai, Japan
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Heidari Z, Fallahi J, Sisakht M, Safari F, Hosseini K, Bahmanimehr A, Savardashtaki A, Khajeh S, Tabei SMB, Razban V. Impact of Tissue Factor Gene Knockout on Coagulation Properties of Umbilical Cord-Derived Multipotent Mesenchymal Stromal/Stem Cells. Cell Biochem Funct 2024; 42:e70021. [PMID: 39660566 DOI: 10.1002/cbf.70021] [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: 08/14/2024] [Revised: 10/18/2024] [Accepted: 11/15/2024] [Indexed: 12/12/2024]
Abstract
Multipotent mesenchymal stromal/stem cells (MSCs) refer to a population of stem cells that exhibit distinct progenitor cell characteristics including the potential for differentiation into a wide range of cell types. MSCs have become a promising candidate for cell therapy and tissue regeneration due to their unique properties, such as their ability to differentiate into multiple cell types, their capacity for expansion, self-renewal, and immune-regulatory effects. However, reports have brought attention to thrombosis-related complications associated with MSCs therapy in the last decade. As tissue factor (TF) is a powerful coagulation activator expressed by MSCs that stimulates the extrinsic coagulation pathway, we investigated the thrombotic properties of human umbilical cord MSCs (HUCMSCs) after knocking out the TF gene. MSCs populations that obtained from umbilical cord were cultured and expanded in the appropriate medium cell culture. The identity of the MSCs was verified through flow cytometry, and their ability to differentiate into osteogenic and adipogenic lineages. Two gRNAs for Exons 1 and 2 of the TF gene have been designed and cloned into px458 vector's backbone (pSpCas9 (BB)-2A-GFP). Following transfecting of gRNAs into HUCMSCs and successfully knocking out the TF gene using GAP-PCR, the impact of normal and knockout HUCMSCs on coagulation was assessed through prothrombin time (PT), D-dimer level, clotting time (CT), and turbidity assay. Furthermore, the impact of TF knockout (TFKO) on MMP19 expression was assessed. Our results revealed that the PT was prolonged and D-dimer level was decreased in TFKO group compared to normal HUCMSCs. These findings suggest that TF gene plays a crucial role in regulating coagulation in HUCMSCs. Also, a significant reduction in MMP19 expression was observed within the TFKO group.
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Affiliation(s)
- Zahra Heidari
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Jafar Fallahi
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohsen Sisakht
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Safari
- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Kamran Hosseini
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ardeshir Bahmanimehr
- Thalassemia and Hemophilia Genetic, PND Research Center, Dastgheib Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Savardashtaki
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- Infertility Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sahar Khajeh
- Orthopedic & Rehabilitation Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Vahid Razban
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- Stem Cell Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Yıldırım Ş, Kandırıcı A. Multipotent mesenchymal stromal cell therapy for a neonate with congenital diaphragmatic hernia and adhesive small bowel obstruction. Turk J Pediatr 2024; 66:630-636. [PMID: 39582451 DOI: 10.24953/turkjpediatr.2024.4856] [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: 06/18/2024] [Accepted: 10/01/2024] [Indexed: 11/26/2024]
Abstract
BACKGROUND In the last decade, therapy using multipotent mesenchymal stromal cells (MSCs) has offered hope for regenerating the lungs of preterm babies with chronic lung disease. Due to similar disease mechanisms, it is logical to explore the potential impact of MSC therapy on pulmonary hypoplasia in congenital diaphragmatic hernia. Furthermore, MSCs may also contribute to the regeneration of the intestines affected by adhesive small bowel obstruction in patients with congenital diaphragmatic hernia. CASE PRESENTATION A female newborn, delivered at 32 weeks and six days gestational age, was diagnosed with a left congenital diaphragmatic hernia. After surgical repair and respiratory/nutritional support for 39 days, she was still dependent on a ventilator and total parenteral nutrition. Two MSC treatments were given a week apart: 10 million cells/kg intratracheally and 5 million cells/kg intravenously. She was extubated, and her enteral nutrition improved after the treatment. No side effects were detected. We present the first documented case using MSCs derived from the umbilical cord to simultaneously treat pulmonary hypoplasia and adhesive small bowel obstruction of congenital diaphragmatic hernia. CONCLUSION Although MSC treatment is very promising for pulmonary hypoplasia and adhesive small bowel disease of congenital diaphragmatic hernia, much more needs to be learned about potential side effects, appropriate dosage, and the optimal method of administration.
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Affiliation(s)
- Şükran Yıldırım
- Department of Neonatology, Prof. Dr. Cemil Taşcıoğlu City Hospital, University of Health Sciences, İstanbul, Türkiye
| | - Aliye Kandırıcı
- Department of Pediatric Surgery, Prof. Dr. Cemil Taşcıoğlu City Hospital, University of Health Sciences, İstanbul, Türkiye
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Hao X, Zhu H, Qin C, Li L, Lin Z, Jiang H, Li Q, Huo Y, Zhang H, Geng X, Huang Y, Li B. Study on Preclinical Safety and Toxic Mechanism of Human Umbilical Cord Mesenchymal Stem Cells in F344RG Rats. Stem Cell Rev Rep 2024; 20:2236-2252. [PMID: 39243336 PMCID: PMC11554750 DOI: 10.1007/s12015-024-10780-w] [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] [Accepted: 08/18/2024] [Indexed: 09/09/2024]
Abstract
Mesenchymal stem cells have made remarkable progress in recent years. Many studies have reported that human umbilical cord mesenchymal stem cells (hUC-MSCs) have no toxicity, but thromboembolism appeared in patients treated with hUC-MSCs. Therefore, people are still worried about the safety of clinical application. The study aims to determine the safety, potential toxic mechanism and biodistribution of hUC-MSCs. F344RG rats were given 5 or 50 million cells/kg of hUC-MSCs by single administration in compliance with Good Laboratory Practice standards. Standard toxicity was performed. RNA sequencing was then performed to explore the potential toxic mechanisms. In parallel, the biodistribution of hUC-MSCs was examined. The dose of 5 million cells/kg hUC-MSCs had no obvious toxicity on symptom, weight, food intake, hematology, serum biochemistry, urine biochemistry, cytokines, and histopathology. However, blood-tinged secretions in the urethral orifice and 20% mortality occurred at 50 million cells/kg. Disseminated intravascular coagulopathy (DIC) is the leading cause of death. hUC-MSCs significantly upregulated complement and coagulation cascade pathways gene expression, resulting in DIC. Besides, hUC-MSCs upregulated fibrinolytic system suppressor genes A2m, Serping1 and Serpinf2. hUC-MSCs survived in rats for less than 28 days, no hUC-MSC was detected in tissues outside the lungs. There was no toxicity in F344RG rats at 5 million cells/kg, but some toxicities were detected at 50 million cells/kg. hUC-MSCs significantly upregulated complement and coagulation cascade pathways, upregulated the expression of fibrinolytic system suppressor genes A2m, Serping1 and Serpinf2, to inhibit fibrinolytic system, caused DIC, which provided a new insight into the toxic mechanism of hUC-MSCs.
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Affiliation(s)
- Xiaofang Hao
- National Institutes for Food and Drug Control, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China
| | - Hao Zhu
- Sinoneural Cell Engineering Group Co., Ltd, Shanghai, China
| | - Chao Qin
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China
| | - Lulu Li
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China
| | - Zhi Lin
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China
| | - Hua Jiang
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China
| | - Qianqian Li
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China
| | - Yan Huo
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China
| | - Hezhan Zhang
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China
| | - Xingchao Geng
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China
| | - Ying Huang
- National Institutes for Food and Drug Control, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China.
| | - Bo Li
- National Institutes for Food and Drug Control, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
- National Institutes for Food and Drug Control, National Center for Safety Evaluation of Drugs, Key Laboratory of Beijing for Safety Evaluation of Drugs, Beijing, China.
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Alaghawani NA, Alkhatib H, Elmancy L, Daou A. Harmonizing Innovations: An In-Depth Comparative Review on the Formulation, Applications, and Future Perspectives of Aerogels and Hydrogels in Pharmaceutical Sciences. Gels 2024; 10:663. [PMID: 39451316 PMCID: PMC11507152 DOI: 10.3390/gels10100663] [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: 04/30/2024] [Revised: 08/21/2024] [Accepted: 09/04/2024] [Indexed: 10/26/2024] Open
Abstract
Gels, specifically hydrogels and aerogels, have emerged as versatile materials with profound implications in pharmaceutical sciences. This comprehensive review looks into detail at hydrogels and aerogels, providing a general introduction to gels as a foundation. The paper is then divided into distinct sections for hydrogels and aerogels, each delving into their unique formulations, advantages, disadvantages, and applications. In the realm of hydrogels, we scrutinize the intricacies of formulation, highlighting the versatile advantages they offer. Conversely, potential limitations are explored, paving the way for a detailed discussion on their applications, with a specific focus on their role in antimicrobial applications. Shifting focus to aerogels, a thorough overview is presented, followed by a detailed explanation of the complex formulation process involving sol-gel chemistry; aging; solvent exchange; and drying techniques, including freeze drying, supercritical drying, and ambient-pressure drying (APD). The intricacies of drug loading and release from aerogels are addressed, providing insights into their pharmaceutical potential. The advantages and disadvantages of aerogels are examined, accompanied by an exploration of their applications, with a specific emphasis on antimicrobial uses. The review culminates in a comparative analysis, juxtaposing the advantages and disadvantages of hydrogels and aerogels. Furthermore, the current research and development trends in the applications of these gels in pharmaceutical sciences are discussed, providing a holistic view of their potential and impact. This review serves as a comprehensive guide for researchers, practitioners, and enthusiasts, seeking a deeper understanding of the distinctive attributes and applications of hydrogels and aerogels in the ever-evolving research concerning pharmaceutical sciences.
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Affiliation(s)
| | | | | | - Anis Daou
- Pharmaceutical Sciences Department, College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (N.A.A.); (H.A.); (L.E.)
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Daga KR, Larey AM, Morfin MG, Chen K, Bitarafan S, Carpenter JM, Hynds HM, Hines KM, Wood LB, Marklein RA. Microglia morphological response to mesenchymal stromal cell extracellular vesicles demonstrates EV therapeutic potential for modulating neuroinflammation. J Biol Eng 2024; 18:58. [PMID: 39420399 PMCID: PMC11488223 DOI: 10.1186/s13036-024-00449-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 09/16/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND Mesenchymal stromal cell derived extracellular vesicles (MSC-EVs) are a promising therapeutic for neuroinflammation. MSC-EVs can interact with microglia, the resident immune cells of the brain, to exert their immunomodulatory effects. In response to inflammatory cues, such as cytokines, microglia undergo phenotypic changes indicative of their function e.g. morphology and secretion. However, these changes in response to MSC-EVs are not well understood. Additionally, no disease-relevant screening tools to assess MSC-EV bioactivity exist, which has further impeded clinical translation. Here, we developed a quantitative, high throughput morphological profiling approach to assess the response of microglia to neuroinflammation- relevant signals and whether this morphological response can be used to indicate the bioactivity of MSC-EVs. RESULTS Using an immortalized human microglia cell-line, we observed increased size (perimeter, major axis length) and complexity (form factor) upon stimulation with interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Upon treatment with MSC-EVs, the overall morphological score (determined using principal component analysis) shifted towards the unstimulated morphology, indicating that MSC-EVs are bioactive and modulate microglia. The morphological effects of MSC-EVs in TNF-α /IFN-γ stimulated cells were concomitant with reduced secretion of 14 chemokines/cytokines (e.g. CXCL6, CXCL9) and increased secretion of 12 chemokines/cytokines (e.g. CXCL8, CXCL10). Proteomic analysis of cell lysates revealed significant increases in 192 proteins (e.g. HIBADH, MEAK7, LAMC1) and decreases in 257 proteins (e.g. PTEN, TOM1, MFF) with MSC-EV treatment. Of note, many of these proteins are involved in regulation of cell morphology and migration. Gene Set Variation Analysis revealed upregulation of pathways associated with immune response, such as regulation of cytokine production, immune cell infiltration (e.g. T cells, NK cells) and morphological changes (e.g. Semaphorin, RHO/Rac signaling). Additionally, changes in microglia mitochondrial morphology were measured suggesting that MSC-EV modulate mitochondrial metabolism. CONCLUSION This study comprehensively demonstrates the effects of MSC-EVs on human microglial morphology, cytokine secretion, cellular proteome, and mitochondrial content. Our high-throughput, rapid, low-cost morphometric approach enables screening of MSC-EV batches and manufacturing conditions to enhance EV function and mitigate EV functional heterogeneity in a disease relevant manner. This approach is highly generalizable and can be further adapted and refined based on selection of the disease-relevant signal, target cell, and therapeutic product.
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Affiliation(s)
- Kanupriya R Daga
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
| | - Andrew M Larey
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
| | - Maria G Morfin
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA
| | - Kailin Chen
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
- Franklin College of Arts and Sciences, University of Georgia, Athens, GA, USA
| | - Sara Bitarafan
- George W. Woodruff School of Mechanical Engineering and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | | | - Hannah M Hynds
- Department of Chemistry, University of Georgia, Athens, GA, USA
| | - Kelly M Hines
- Department of Chemistry, University of Georgia, Athens, GA, USA
| | - Levi B Wood
- George W. Woodruff School of Mechanical Engineering and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Ross A Marklein
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA.
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA.
- Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD, 20903, USA.
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Karpf S, Glöckner Burmeister N, Dubreil L, Ghosh S, Hollandi R, Pichon J, Leroux I, Henkel A, Lutz V, Jurkevičius J, Latshaw A, Kilin V, Kutscher T, Wiggert M, Saavedra-Villanueva O, Vogel A, Huber RA, Horvath P, Rouger K, Bonacina L. Harmonic Imaging of Stem Cells in Whole Blood at GHz Pixel Rate. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2401472. [PMID: 38863131 DOI: 10.1002/smll.202401472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 05/21/2024] [Indexed: 06/13/2024]
Abstract
The pre-clinical validation of cell therapies requires monitoring the biodistribution of transplanted cells in tissues of host organisms. Real-time detection of these cells in the circulatory system and identification of their aggregation state is a crucial piece of information, but necessitates deep penetration and fast imaging with high selectivity, subcellular resolution, and high throughput. In this study, multiphoton-based in-flow detection of human stem cells in whole, unfiltered blood is demonstrated in a microfluidic channel. The approach relies on a multiphoton microscope with diffractive scanning in the direction perpendicular to the flow via a rapidly wavelength-swept laser. Stem cells are labeled with metal oxide harmonic nanoparticles. Thanks to their strong and quasi-instantaneous second harmonic generation (SHG), an imaging rate in excess of 10 000 frames per second is achieved with pixel dwell times of 1 ns, a duration shorter than typical fluorescence lifetimes yet compatible with SHG. Through automated cell identification and segmentation, morphological features of each individual detected event are extracted and cell aggregates are distinguished from isolated cells. This combination of high-speed multiphoton microscopy and high-sensitivity SHG nanoparticle labeling in turbid media promises the detection of rare cells in the bloodstream for assessing novel cell-based therapies.
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Affiliation(s)
- Sebastian Karpf
- Institute of Biomedical Optics (BMO), University Of Luebeck, 23562, Luebeck, Germany
| | | | | | - Shayantani Ghosh
- Department of Applied Physics, Université de Genève, Rue de l'Ecole-de-Médecine, 20, Geneva, 1205, Switzerland
| | - Reka Hollandi
- Synthetic and Systems Biology Unit, Biological Research Centre (BRC), Szeged, H-6726, Hungary
| | | | | | - Alessandra Henkel
- Institute of Biomedical Optics (BMO), University Of Luebeck, 23562, Luebeck, Germany
| | - Valerie Lutz
- Institute of Biomedical Optics (BMO), University Of Luebeck, 23562, Luebeck, Germany
| | - Jonas Jurkevičius
- Institute of Biomedical Optics (BMO), University Of Luebeck, 23562, Luebeck, Germany
| | - Alexandra Latshaw
- Department of Applied Physics, Université de Genève, Rue de l'Ecole-de-Médecine, 20, Geneva, 1205, Switzerland
| | - Vasyl Kilin
- Department of Applied Physics, Université de Genève, Rue de l'Ecole-de-Médecine, 20, Geneva, 1205, Switzerland
| | - Tonio Kutscher
- Institute of Biomedical Optics (BMO), University Of Luebeck, 23562, Luebeck, Germany
| | - Moritz Wiggert
- Department of Applied Physics, Université de Genève, Rue de l'Ecole-de-Médecine, 20, Geneva, 1205, Switzerland
| | | | - Alfred Vogel
- Institute of Biomedical Optics (BMO), University Of Luebeck, 23562, Luebeck, Germany
| | - Robert A Huber
- Institute of Biomedical Optics (BMO), University Of Luebeck, 23562, Luebeck, Germany
| | - Peter Horvath
- Synthetic and Systems Biology Unit, Biological Research Centre (BRC), Szeged, H-6726, Hungary
| | - Karl Rouger
- Oniris, INRAE, PAnther, Nantes, F-44307, France
| | - Luigi Bonacina
- Department of Applied Physics, Université de Genève, Rue de l'Ecole-de-Médecine, 20, Geneva, 1205, Switzerland
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Wang Z, Yang C, Yan S, Sun J, Zhang J, Qu Z, Sun W, Zang J, Xu D. Emerging Role and Mechanism of Mesenchymal Stem Cells-Derived Extracellular Vesicles in Rheumatic Disease. J Inflamm Res 2024; 17:6827-6846. [PMID: 39372581 PMCID: PMC11451471 DOI: 10.2147/jir.s488201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 09/20/2024] [Indexed: 10/08/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are pluripotent stem cells derived from mesoderm. Through cell-to-cell contact or paracrine effects, they carry out biological tasks like immunomodulatory, anti-inflammatory, regeneration, and repair. Extracellular vesicles (EVs) are the primary mechanism for the paracrine regulation of MSCs. They deliver proteins, nucleic acids, lipids, and other active compounds to various tissues and organs, thus facilitating intercellular communication. Rheumatic diseases may be treated using MSCs and MSC-derived EVs (MSC-EVs) due to their immunomodulatory capabilities, according to mounting data. Since MSC-EVs have low immunogenicity, high stability, and similar biological effects as to MSCs themselves, they are advantageous over cell therapy for potential therapeutic applications in rheumatoid arthritis, systemic erythematosus lupus, systemic sclerosis, Sjogren's syndrome, and other rheumatoid diseases. This review integrates recent advances in the characteristics, functions, and potential molecular mechanisms of MSC-EVs in rheumatic diseases and provides a new understanding of the pathogenesis of rheumatic diseases and MSC-EV-based treatment strategies.
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Affiliation(s)
- Zhangxue Wang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, 261000, People’s Republic of China
- Department of Rheumatology and Immunology, Weifang People’s Hospital, Shandong Second Medical University, Weifang, Shandong, 261000, People’s Republic of China
| | - Chunjuan Yang
- Central Laboratory, Weifang People’s Hospital, Shandong Second Medical University, Weifang, Shandong, 261000, People’s Republic of China
| | - Shushan Yan
- Department of Gastrointestinal and Anal Diseases Surgery, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, 261000, People’s Republic of China
| | - Jiamei Sun
- Central Laboratory, Weifang People’s Hospital, Shandong Second Medical University, Weifang, Shandong, 261000, People’s Republic of China
| | - Jin Zhang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, 261000, People’s Republic of China
- Department of Rheumatology and Immunology, Weifang People’s Hospital, Shandong Second Medical University, Weifang, Shandong, 261000, People’s Republic of China
| | - Zhuojian Qu
- School of Basic Medicine Sciences, Shandong Second Medical University, Weifang, Shandong, 261000, People’s Republic of China
| | - Wenchang Sun
- Central Laboratory, Weifang People’s Hospital, Shandong Second Medical University, Weifang, Shandong, 261000, People’s Republic of China
| | - Jie Zang
- Central Laboratory, Weifang People’s Hospital, Shandong Second Medical University, Weifang, Shandong, 261000, People’s Republic of China
| | - Donghua Xu
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, 261000, People’s Republic of China
- Department of Rheumatology and Immunology, Weifang People’s Hospital, Shandong Second Medical University, Weifang, Shandong, 261000, People’s Republic of China
- Central Laboratory, Weifang People’s Hospital, Shandong Second Medical University, Weifang, Shandong, 261000, People’s Republic of China
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Lu R, Zheng K, Zhou Y, Wang W, Zhang Y, Chen Y, Mo M, Li X, Dong Y, Xie J, Zhang H, Yang Q, Wang G, Zhao Y, Wu Y. 3D spheroid culture synchronizes heterogeneous MSCs into an immunomodulatory phenotype with enhanced anti-inflammatory effects. iScience 2024; 27:110811. [PMID: 39286508 PMCID: PMC11404176 DOI: 10.1016/j.isci.2024.110811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 07/16/2024] [Accepted: 08/21/2024] [Indexed: 09/19/2024] Open
Abstract
Mesenchymal stem cells (MSCs) are heterogeneous in morphology and transcriptome, resulting in varying therapeutic outcomes. In this study, we found that 3D spheroid culture of heterogeneous MSCs, which have undergone conventional 2D monolayer culture for 5-6 passages, synchronized the cells into a uniform cell population with dramatically reduced cell size, and considerably increased levels of immunosuppressive genes and growth factors. Single-cell RNA sequencing (scRNA-seq) analysis of the cells revealed that 3D MSCs consisted of 2 major cell subpopulations and both expressed high levels of immunosuppressive factors, compared to 6 subpopulations in 2D MSCs. In addition, 3D MSCs showed a greater suppressive effect on T cells. Moreover, intravenous infusion of a large dose of 3D MSCs prior to imiquimod (IMQ) treatment significantly improved psoriatic lesion. Thus, our results indicate that 3D spheroid culture reprograms heterogeneous MSCs into a uniform immunosuppressive phenotype and promises a novel therapeutic potential for inflammatory diseases.
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Affiliation(s)
- Ruiqing Lu
- State Key Laboratory of Chemical Oncogenomics, and Institute of Biopharmaceutical and Health Engineering (iBHE), Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Ke Zheng
- State Key Laboratory of Chemical Oncogenomics, and Institute of Biopharmaceutical and Health Engineering (iBHE), Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Yongjie Zhou
- State Key Laboratory of Chemical Oncogenomics, and Institute of Biopharmaceutical and Health Engineering (iBHE), Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Weibu Wang
- State Key Laboratory of Chemical Oncogenomics, and Institute of Biopharmaceutical and Health Engineering (iBHE), Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Yanan Zhang
- State Key Laboratory of Chemical Oncogenomics, and Institute of Biopharmaceutical and Health Engineering (iBHE), Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Yu Chen
- State Key Laboratory of Chemical Oncogenomics, and Institute of Biopharmaceutical and Health Engineering (iBHE), Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Miaohua Mo
- Department of Biotechnology, Guangdong Medical University, Dongguan 523808, China
| | - Xiaosong Li
- State Key Laboratory of Chemical Oncogenomics, and Institute of Biopharmaceutical and Health Engineering (iBHE), Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Yankai Dong
- State Key Laboratory of Chemical Oncogenomics, and Institute of Biopharmaceutical and Health Engineering (iBHE), Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Jundong Xie
- State Key Laboratory of Chemical Oncogenomics, and Institute of Biopharmaceutical and Health Engineering (iBHE), Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Guojian Qingke Biopharmaceutical Co. Ltd, Beijing 100176, China
| | - Haiji Zhang
- State Key Laboratory of Chemical Oncogenomics, and Institute of Biopharmaceutical and Health Engineering (iBHE), Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Qingyang Yang
- State Key Laboratory of Chemical Oncogenomics, and Institute of Biopharmaceutical and Health Engineering (iBHE), Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen 518055, China
| | - Guoliang Wang
- Guojian Qingke Biopharmaceutical Co. Ltd, Beijing 100176, China
| | - Yi Zhao
- Department of Dermatology, Beijing Tsinghua Changgeng Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
- Photomedicine Laboratory, Institute of Precision Medicine, Tsinghua University, Beijing 102218, China
| | - Yaojiong Wu
- State Key Laboratory of Chemical Oncogenomics, and Institute of Biopharmaceutical and Health Engineering (iBHE), Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen 518055, China
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11
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Ore A, Angelastro JM, Giulivi C. Integrating Mitochondrial Biology into Innovative Cell Therapies for Neurodegenerative Diseases. Brain Sci 2024; 14:899. [PMID: 39335395 PMCID: PMC11429837 DOI: 10.3390/brainsci14090899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 08/31/2024] [Accepted: 09/03/2024] [Indexed: 09/30/2024] Open
Abstract
The role of mitochondria in neurodegenerative diseases is crucial, and recent developments have highlighted its significance in cell therapy. Mitochondrial dysfunction has been implicated in various neurodegenerative disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's diseases. Understanding the impact of mitochondrial biology on these conditions can provide valuable insights for developing targeted cell therapies. This mini-review refocuses on mitochondria and emphasizes the potential of therapies leveraging mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, stem cell-derived secretions, and extracellular vesicles. Mesenchymal stem cell-mediated mitochondria transfer is highlighted for restoring mitochondrial health in cells with dysfunctional mitochondria. Additionally, attention is paid to gene-editing techniques such as mito-CRISPR, mitoTALENs, mito-ZNFs, and DdCBEs to ensure the safety and efficacy of stem cell treatments. Challenges and future directions are also discussed, including the possible tumorigenic effects of stem cells, off-target effects, disease targeting, immune rejection, and ethical issues.
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Affiliation(s)
- Adaleiz Ore
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA; (A.O.); (J.M.A.)
- Department of Chemical Engineering, School of Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
| | - James M. Angelastro
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA; (A.O.); (J.M.A.)
| | - Cecilia Giulivi
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA; (A.O.); (J.M.A.)
- University of California Medical Investigations of Neurodevelopmental Disorders Institute (MIND Institute), University of California Health, Sacramento, CA 95817, USA
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12
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Kim M, Choi H, Jang DJ, Kim HJ, Sub Y, Gee HY, Choi C. Exploring the clinical transition of engineered exosomes designed for intracellular delivery of therapeutic proteins. Stem Cells Transl Med 2024; 13:637-647. [PMID: 38838263 PMCID: PMC11227971 DOI: 10.1093/stcltm/szae027] [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: 11/13/2023] [Accepted: 03/18/2024] [Indexed: 06/07/2024] Open
Abstract
Extracellular vesicles, particularly exosomes, have emerged as promising drug delivery systems owing to their unique advantages, such as biocompatibility, immune tolerability, and target specificity. Various engineering strategies have been implemented to harness these innate qualities, with a focus on enhancing the pharmacokinetic and pharmacodynamic properties of exosomes via payload loading and surface engineering for active targeting. This concise review outlines the challenges in the development of exosomes as drug carriers and offers insights into strategies for their effective clinical translation. We also highlight preclinical studies that have successfully employed anti-inflammatory exosomes and suggest future directions for exosome therapeutics. These advancements underscore the potential for integrating exosome-based therapies into clinical practice, heralding promise for future medical interventions.
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Affiliation(s)
| | - Hojun Choi
- ILIAS Biologics Inc., Daejeon 34014, Korea
| | - Deok-Jin Jang
- ILIAS Biologics Inc., Daejeon 34014, Korea
- Department of Ecological Science, College of Ecology and Environment, Kyungpook National University, Sangju 37224, Korea
| | | | - Yujin Sub
- Department of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Heon Yung Gee
- Department of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
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Daga KR, Larey AM, Morfin MG, Chen K, Bitarafan S, Carpenter JM, Hynds HM, Hines KM, Wood LB, Marklein RA. Microglia Morphological Response to Mesenchymal Stromal Cell Extracellular Vesicles Demonstrates EV Therapeutic Potential for Modulating Neuroinflammation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.01.601612. [PMID: 39005342 PMCID: PMC11245023 DOI: 10.1101/2024.07.01.601612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
Background Mesenchymal stromal cell derived extracellular vesicles (MSC-EVs) are a promising therapeutic for neuroinflammation. MSC-EVs can interact with microglia, the resident immune cells of the brain, to exert their immunomodulatory effects. In response to inflammatory cues, such as cytokines, microglia undergo phenotypic changes indicative of their function e.g. morphology and secretion. However, these changes in response to MSC-EVs are not well understood. Additionally, no disease-relevant screening tools to assess MSC-EV bioactivity exist, which has further impeded clinical translation. Here, we developed a quantitative, high throughput morphological profiling approach to assess the response of microglia to neuroinflammation-relevant signals and whether this morphological response can be used to indicate the bioactivity of MSC-EVs. Results Using an immortalized human microglia cell-line, we observed increased size (perimeter, major axis length) and complexity (form factor) upon stimulation with interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Upon treatment with MSC-EVs, the overall morphological score (determined using principal component analysis) shifted towards the unstimulated morphology, indicating that MSC-EVs are bioactive and modulate microglia. The morphological effects of MSC-EVs in TNF-γ/IFN-α stimulated cells were concomitant with reduced secretion of 14 chemokines/cytokines (e.g. CXCL6, CXCL9) and increased secretion of 12 chemokines/cytokines (e.g. CXCL8, CXCL10). Proteomic analysis of cell lysates revealed significant increases in 192 proteins (e.g. HIBADH, MEAK7, LAMC1) and decreases in 257 proteins (e.g. PTEN, TOM1, MFF) with MSC-EV treatment. Of note, many of these proteins are involved in regulation of cell morphology and migration. Gene Set Variation Analysis revealed upregulation of pathways associated with immune response, such as regulation of cytokine production, immune cell infiltration (e.g. T cells, NK cells) and morphological changes (e.g. Semaphorin, RHO/Rac signaling). Additionally, changes in microglia mitochondrial morphology were measured suggesting that MSC-EV modulate mitochondrial metabolism. Conclusion This study comprehensively demonstrates the effects of MSC-EVs on human microglial morphology, cytokine secretion, cellular proteome, and mitochondrial content. Our high-throughput, rapid, low-cost morphological approach enables screening of MSC-EV batches and manufacturing conditions to enhance EV function and mitigate EV functional heterogeneity in a disease relevant manner. This approach is highly generalizable and can be further adapted and refined based on selection of the disease-relevant signal, target cell, and therapeutic product.
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Affiliation(s)
- Kanupriya R Daga
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
| | - Andrew M Larey
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
| | - Maria G Morfin
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA
| | - Kailin Chen
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
- Franklin College of Arts and Sciences, University of Georgia, Athens, GA, USA
| | - Sara Bitarafan
- George W. Woodruff School of Mechanical Engineering and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | | | - Hannah M Hynds
- Department of Chemistry, University of Georgia, Athens, GA, USA
| | - Kelly M Hines
- Department of Chemistry, University of Georgia, Athens, GA, USA
| | - Levi B Wood
- George W. Woodruff School of Mechanical Engineering and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Ross A Marklein
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, USA
- Regenerative Bioscience Center, University of Georgia, Athens, GA, USA
- Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
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14
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Panos LD, Bargiotas P, Arnold M, Hadjigeorgiou G, Panos GD. Revolutionizing Stroke Recovery: Unveiling the Promise of Stem Cell Therapy. Drug Des Devel Ther 2024; 18:991-1006. [PMID: 38567255 PMCID: PMC10986404 DOI: 10.2147/dddt.s460998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 03/26/2024] [Indexed: 04/04/2024] Open
Abstract
Stem cells, renowned for their unique regenerative capabilities, present significant hope in treating stroke, a major cause of disability globally. This review offers a detailed analysis of stem cell applications in stroke (ischemic and hemorrhagic) recovery. It examines therapies based on autologous (patient-derived), allogeneic (donor-derived), and Granulocyte-Colony Stimulating Factor (G-CSF) based stem cells, focusing on cell types such as Mesenchymal Stem/Stromal Cells (MSCs), Bone Marrow Mononuclear Stem Cells (BMMSCs), and Neural Stem/Progenitor Cells (NSCs). The paper compiles clinical trial data to evaluate their effectiveness and safety and addresses the ethical concerns of these innovative treatments. By explaining the mechanisms of stem cell-induced neurological repair, this review underscores stem cells' potential in revolutionizing stroke rehabilitation and suggests avenues for future research.
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Affiliation(s)
- Leonidas D Panos
- Department of Neurology, Bern University Hospital Inselspital, Bern, Switzerland
- Department of Neurology, School of Medicine, University of Cyprus, Nicosia, Cyprus
| | - Panagiotis Bargiotas
- Department of Neurology, School of Medicine, University of Cyprus, Nicosia, Cyprus
| | - Marcel Arnold
- Department of Neurology, Bern University Hospital Inselspital, Bern, Switzerland
| | | | - Georgios D Panos
- Department of Ophthalmology, Queen’s Medical Centre, Nottingham University Hospitals (NUH), Nottingham, UK
- Division of Ophthalmology and Visual Sciences, School of Medicine, University of Nottingham, Nottingham, UK
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Hoang VT, Le DS, Hoang DM, Phan TTK, Ngo LAT, Nguyen TK, Bui VA, Nguyen Thanh L. Impact of tissue factor expression and administration routes on thrombosis development induced by mesenchymal stem/stromal cell infusions: re-evaluating the dogma. Stem Cell Res Ther 2024; 15:56. [PMID: 38414067 PMCID: PMC10900728 DOI: 10.1186/s13287-023-03582-3] [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: 05/22/2023] [Accepted: 11/22/2023] [Indexed: 02/29/2024] Open
Abstract
BACKGROUND Hyperactive coagulation might cause dangerous complications such as portal vein thrombosis and pulmonary embolism after mesenchymal stem/stromal cell (MSC) therapy. Tissue factor (TF), an initiator of the extrinsic coagulation pathway, has been suggested as a predictor of this process. METHODS The expression of TF and other pro- and anticoagulant genes was analyzed in xeno- and serum-free manufactured MSCs. Furthermore, culture factors affecting its expression in MSCs were investigated. Finally, coagulation tests of fibrinogen, D-dimer, aPPTs, PTs, and TTs were measured in patient serum after umbilical cord (UC)-MSC infusions to challenge a potential connection between TF expression and MSC-induced coagulant activity. RESULTS: Xeno- and serum-free cultured adipose tissue and UC-derived MSCs expressed the highest level of TF, followed by those from dental pulp, and the lowest expression was observed in MSCs of bone marrow origin. Environmental factors such as cell density, hypoxia, and inflammation impact TF expression, so in vitro analysis might fail to reflect their in vivo behaviors. MSCs also expressed heterogeneous levels of the coagulant factor COL1A1 and surface phosphatidylserine and anticoagulant factors TFPI and PTGIR. MSCs of diverse origins induced fibrin clots in healthy plasma that were partially suppressed by an anti-TF inhibitory monoclonal antibody. Furthermore, human umbilical vein endothelial cells exhibited coagulant activity in vitro despite their negative expression of TF and COL1A1. Patients receiving intravenous UC-MSC infusion exhibited a transient increase in D-dimer serum concentration, while this remained stable in the group with intrathecal infusion. There was no correlation between TF expression and D-dimer or other coagulation indicators. CONCLUSIONS The study suggests that TF cannot be used as a solid biomarker to predict MSC-induced hypercoagulation. Local administration, prophylactic intervention with anticoagulation drugs, and monitoring of coagulation indicators are useful to prevent thrombogenic events in patients receiving MSCs. Trial registration NCT05292625. Registered March 23, 2022, retrospectively registered, https://www. CLINICALTRIALS gov/ct2/show/NCT05292625?term=NCT05292625&draw=2&rank=1 . NCT04919135. Registered June 9, 2021, https://www. CLINICALTRIALS gov/ct2/show/NCT04919135?term=NCT04919135&draw=2&rank=1 .
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Affiliation(s)
- Van T Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, 458 Minh Khai, Hai Ba Trung District, Hanoi, 100000, Vietnam.
| | - Duc Son Le
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, 458 Minh Khai, Hai Ba Trung District, Hanoi, 100000, Vietnam
| | - Duc M Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, 458 Minh Khai, Hai Ba Trung District, Hanoi, 100000, Vietnam
| | - Trang Thi Kieu Phan
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, 458 Minh Khai, Hai Ba Trung District, Hanoi, 100000, Vietnam
| | - Lan Anh Thi Ngo
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, 458 Minh Khai, Hai Ba Trung District, Hanoi, 100000, Vietnam
- Center of Applied Science and Regenerative Medicine, Vinmec Health Care System, 458 Minh Khai, Hanoi, 10000, Vietnam
| | - Trung Kien Nguyen
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, 458 Minh Khai, Hai Ba Trung District, Hanoi, 100000, Vietnam
| | - Viet Anh Bui
- Center of Applied Science and Regenerative Medicine, Vinmec Health Care System, 458 Minh Khai, Hanoi, 10000, Vietnam
| | - Liem Nguyen Thanh
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, 458 Minh Khai, Hai Ba Trung District, Hanoi, 100000, Vietnam.
- Vinmec International Hospital - Times City, Vinmec Health Care System, 458 Minh Khai, Hanoi, 11622, Vietnam.
- College of Health Science, VinUniversity, Vinhomes Ocean Park, Gia Lam District, Hanoi, 1310, Vietnam.
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Schriner JB, Triolo F, Gill BS, Cardenas JC, Olson SD, Cox CS. Low molecular weight heparin decreases pro-coagulant activity in clinical MSC products. Cytotherapy 2024; 26:194-200. [PMID: 38127031 PMCID: PMC11350517 DOI: 10.1016/j.jcyt.2023.11.010] [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: 08/27/2023] [Revised: 11/15/2023] [Accepted: 11/19/2023] [Indexed: 12/23/2023]
Abstract
BACKGROUND AIMS Mesenchymal stromal cells (MSCs) are multipotent adult cells that can be isolated from tissues including bone marrow [MSC(BM)], adipose [MSC(AT)] and umbilical cord [MSC(CT)]. Previous studies have linked expression of tissue factor (TF) on MSC surfaces to a procoagulant effect. Venous thromboembolism (VTE), immediate blood-mediated inflammatory reaction (IBMIR) and microvascular thrombosis remain a risk with intravascular MSC therapy. We examined the effect of low molecular weight heparin (LMWH) on clinical-grade MSCs using calibrated automated thrombography (CAT). METHODS Clinical grade MSC(BM)s, MSC(AT)s and MSC(CT)s harvested at passage 4 were added to normal pooled plasma (NPP) to a final concentration of either 400 000 or 50 000 cells/mL. LMWH was added to plasma in increments of 0.1 U/mL. Thrombin generation (TG) was measured using CAT. Flow cytometry was conducted on the cells to measure MSC phenotype and TF load. RESULTS Presence of MSCs decreased lag time and increased peak TG. All cell lines demonstrated a dose response to LMWH, with MSC(AT) demonstrating the least thrombogenicity and most sensitivity to LMWH. TG was significantly reduced in all cell lines at doses of 0.2 U/mL LMWH and higher. DISCUSSION All MSC types and concentrations had a decrease in peak thrombin and TG with increasing amounts of LMWH. While this in vitro study cannot determine optimal dosing, it suggests that LMWH can be effectively used to lower the risk of VTE associated with intravascular administration of MSCs. Future in vivo work can be done to determine optimal dosing and effect on IBMIR and VTE.
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Affiliation(s)
- Jacob B Schriner
- Department of Surgery, Center for Translational Injury Research, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.
| | - Fabio Triolo
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Brijesh S Gill
- Department of Surgery, Center for Translational Injury Research, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA; Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Jessica C Cardenas
- Department of Surgery, Center for Translational Injury Research, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Scott D Olson
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Charles S Cox
- Department of Surgery, Center for Translational Injury Research, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA; Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
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Huang C, Zhao Y, Ye Q, Gleason J, Rousseva V, Stout B, Lin S, Hariri R, Zhang X, He S. Characterization of CRISPR/Cas9-edited human placental allogenic stromal cells with low tissue factor expression and reduced thrombotic effects. Cytotherapy 2023; 25:1265-1270.e2. [PMID: 37256239 DOI: 10.1016/j.jcyt.2023.04.013] [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: 02/10/2023] [Revised: 04/21/2023] [Accepted: 04/28/2023] [Indexed: 06/01/2023]
Abstract
The tissue factor (TF/CD142) expressed by mesenchymal stromal cells (MSCs) has been regarded as a safety concern in clinical applications as it may trigger thrombosis when MSCs administered intravenously. Human placental allogenic stromal cells (ASCs) are culture-expanded, undifferentiated MSC-like cells derived from full-term postpartum placenta and possess immunomodulatory and pro-angiogenic activities, however, express TF. Here we performed CRISPR/Cas9-mediated TF gene knock out (TFKO) in ASCs, leading to significantly lower TF expression, activity and thrombotic effects. ASCs' characteristics including expansion, expression of phenotypic markers and secretory profile remained unchanged in edited cells, and their immunomodulatory activities, which are functionally relevant to therapeutic applications, were not affected upon TFKO. Taken together, this study provides a feasible strategy which could improve the clinical safety features of MSC-based cell therapy by CRISRP/Cas9-mediated TF gene knock out.
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Affiliation(s)
| | | | - Qian Ye
- Celularity Inc., Florham Park, New Jersey, USA
| | | | | | | | | | | | | | - Shuyang He
- Celularity Inc., Florham Park, New Jersey, USA
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Lu B, Lerman LO. MSC therapy for diabetic kidney disease and nephrotic syndrome. Nat Rev Nephrol 2023; 19:754-755. [PMID: 37783947 PMCID: PMC11955841 DOI: 10.1038/s41581-023-00776-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2023]
Affiliation(s)
- Bo Lu
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
- Department of Cardiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
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19
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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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20
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Jurcau A, Andronie-Cioara FL, Nistor-Cseppento DC, Pascalau N, Rus M, Vasca E, Jurcau MC. The Involvement of Neuroinflammation in the Onset and Progression of Parkinson's Disease. Int J Mol Sci 2023; 24:14582. [PMID: 37834030 PMCID: PMC10573049 DOI: 10.3390/ijms241914582] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 09/22/2023] [Accepted: 09/24/2023] [Indexed: 10/15/2023] Open
Abstract
Parkinson's disease is a neurodegenerative disease exhibiting the fastest growth in incidence in recent years. As with most neurodegenerative diseases, the pathophysiology is incompletely elucidated, but compelling evidence implicates inflammation, both in the central nervous system and in the periphery, in the initiation and progression of the disease, although it is not yet clear what triggers this inflammatory response and where it begins. Gut dysbiosis seems to be a likely candidate for the initiation of the systemic inflammation. The therapies in current use provide only symptomatic relief, but do not interfere with the disease progression. Nonetheless, animal models have shown promising results with therapies that target various vicious neuroinflammatory cascades. Translating these therapeutic strategies into clinical trials is still in its infancy, and a series of issues, such as the exact timing, identifying biomarkers able to identify Parkinson's disease in early and pre-symptomatic stages, or the proper indications of genetic testing in the population at large, will need to be settled in future guidelines.
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Affiliation(s)
- Anamaria Jurcau
- Department of Psycho-Neuroscience and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania; (A.J.); (D.C.N.-C.)
| | - Felicia Liana Andronie-Cioara
- Department of Psycho-Neuroscience and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania; (A.J.); (D.C.N.-C.)
| | - Delia Carmen Nistor-Cseppento
- Department of Psycho-Neuroscience and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania; (A.J.); (D.C.N.-C.)
| | - Nicoleta Pascalau
- Department of Psycho-Neuroscience and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania; (A.J.); (D.C.N.-C.)
| | - Marius Rus
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania
| | - Elisabeta Vasca
- Department of Oral Rehabilitation, Faculty of Medicine “Vasile Goldis” Arad, 310025 Arad, Romania
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21
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Arango-Rodríguez ML, Mateus LC, Sossa CL, Becerra-Bayona SM, Solarte-David VA, Ochoa Vera ME, Viviescas LTG, Berrio AMV, Serrano SE, Vargas O, Isla AC, Benitez A, Rangel G. A novel therapeutic management for diabetes patients with chronic limb-threatening ischemia: comparison of autologous bone marrow mononuclear cells versus allogenic Wharton jelly-derived mesenchymal stem cells. Stem Cell Res Ther 2023; 14:221. [PMID: 37626416 PMCID: PMC10464344 DOI: 10.1186/s13287-023-03427-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 07/24/2023] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND Chronic limb-threatening ischemia (CLTI) represents the final stage of peripheral arterial disease. Approximately one-third of patients with CLTI are not eligible for conventional surgical treatments. Furthermore, patients with advanced stage of CLTI are prone to amputation and death. Thus, an effective therapeutic strategy is urgently needed. In this context, autologous bone marrow mononuclear cell (auto-BM-MNC) and allogeneic mesenchymal stem cells represent a promising therapeutic approach for treating CLTI. In this study, we compared the safety and beneficial therapeutic effect of auto-BM-MNC versus allogeneic Wharton jelly-derived mesenchymal stem cells (allo-WJ-MSCs) in diabetic patients with CLTI. METHODS We performed a randomized, prospective, double-blind and controlled pilot study. Twenty-four diabetic patients in the advanced stage of CLTI (4 or 5 in Rutherford's classification) and a transcutaneous oxygen pressure (TcPO2) below 30 mmHg were randomized to receive 15 injections of (i) auto-BM-MNC (7.197 × 106 ± 2.984 × 106 cells/mL) (n = 7), (ii) allo-WJ-MSCs (1.333 × 106 cells/mL) (n = 7) or (iii) placebo solution (1 mL) (n = 10), which were administered into the periadventitial layer of the arterial walls under eco-Doppler guidance. The follow-up visits were at months 1, 3, 6, and 12 to evaluate the following parameters: (i) Rutherford's classification, (ii) TcPO2, (iii) percentage of wound closure, (iv) pain, (v) pain-free walking distance, (vi) revascularization and limb-survival proportion, and (vii) life quality (EQ-5D questionnaire). RESULTS No adverse events were reported. Patients with CLTI who received auto-BM-MNC and allo-WJ-MSCs presented an improvement in Rutherford's classification, a significant increase in TcPO2 values, a reduction in the lesion size in a shorter time, a decrease in the pain score and an increase in the pain-free walking distance, in comparison with the placebo group. In addition, the participants treated with auto-BM-MNC and allo-WJ-MSCs kept their limbs during the follow-up period, unlike the placebo group, which had a marked increase in amputation. CONCLUSIONS Our results showed that patients with CLTI treated with auto-BM-MNC and allo-WJ-MSCs conserved 100% of their limb during 12 months of the follow-up compared to the placebo group, where 60% of participants underwent limb amputation in different times. Furthermore, we observed a faster improvement in the allo-WJ-MSC group, unlike the auto-BM-MNC group. Trial registration This study was retrospectively registered at ClinicalTrials.gov (NCT05631444).
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Affiliation(s)
- Martha L Arango-Rodríguez
- Banco Multitejidos y Centro de Terapias Avanzadas, Clínica FOSCAL Internacional, 681004, Floridablanca, Colombia.
| | - Ligia C Mateus
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
| | - Claudia L Sossa
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
- Programa para el Tratamiento y Estudio de Enfermedades Hematológicas y Oncológicas de Santander (PROTEHOS), 681004153, Floridablanca, Colombia
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
| | - Silvia M Becerra-Bayona
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
| | - Víctor Alfonso Solarte-David
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
- Facultad de Ingeniería, Universidad Autónoma de Bucaramanga - UNAB, 680003, Bucaramanga, Colombia
| | - Miguel Enrique Ochoa Vera
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
| | - Lady T Giratá Viviescas
- Banco Multitejidos y Centro de Terapias Avanzadas, Clínica FOSCAL Internacional, 681004, Floridablanca, Colombia
| | - Ana M Vera Berrio
- Banco Multitejidos y Centro de Terapias Avanzadas, Clínica FOSCAL Internacional, 681004, Floridablanca, Colombia
| | - Sergio Eduardo Serrano
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
| | - Oliverio Vargas
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
| | - Andrés Catalá Isla
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
| | - Alape Benitez
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
| | - Germán Rangel
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
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22
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Khan S, Mahgoub S, Fallatah N, Lalor PF, Newsome PN. Liver Disease and Cell Therapy: Advances Made and Remaining Challenges. Stem Cells 2023; 41:739-761. [PMID: 37052348 PMCID: PMC10809282 DOI: 10.1093/stmcls/sxad029] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 02/27/2023] [Indexed: 04/14/2023]
Abstract
The limited availability of organs for liver transplantation, the ultimate curative treatment for end stage liver disease, has resulted in a growing and unmet need for alternative therapies. Mesenchymal stromal cells (MSCs) with their broad ranging anti-inflammatory and immunomodulatory properties have therefore emerged as a promising therapeutic agent in treating inflammatory liver disease. Significant strides have been made in exploring their biological activity. Clinical application of MSC has shifted the paradigm from using their regenerative potential to one which harnesses their immunomodulatory properties. Reassuringly, MSCs have been extensively investigated for over 30 years with encouraging efficacy and safety data from translational and early phase clinical studies, but questions remain about their utility. Therefore, in this review, we examine the translational and clinical studies using MSCs in various liver diseases and their impact on dampening immune-mediated liver damage. Our key observations include progress made thus far with use of MSCs for clinical use, inconsistency in the literature to allow meaningful comparison between different studies and need for standardized protocols for MSC manufacture and administration. In addition, the emerging role of MSC-derived extracellular vesicles as an alternative to MSC has been reviewed. We have also highlighted some of the remaining clinical challenges that should be addressed before MSC can progress to be considered as therapy for patients with liver disease.
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Affiliation(s)
- Sheeba Khan
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, Birmingham, West Midlands, UK
| | - Sara Mahgoub
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, Birmingham, West Midlands, UK
| | - Nada Fallatah
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Patricia F Lalor
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
| | - Philip N Newsome
- National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham, Birmingham, West Midlands, UK
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, West Midlands, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, Birmingham, West Midlands, UK
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23
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Couto PS, Al-Arawe N, Filgueiras IS, Fonseca DLM, Hinterseher I, Catar RA, Chinnadurai R, Bersenev A, Cabral-Marques O, Moll G, Verter F. Systematic review and meta-analysis of cell therapy for COVID-19: global clinical trial landscape, published safety/efficacy outcomes, cell product manufacturing and clinical delivery. Front Immunol 2023; 14:1200180. [PMID: 37415976 PMCID: PMC10321603 DOI: 10.3389/fimmu.2023.1200180] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 05/24/2023] [Indexed: 07/08/2023] Open
Abstract
During the pandemic of severe respiratory distress syndrome coronavirus 2 (SARS-CoV2), many novel therapeutic modalities to treat Coronavirus 2019 induced disease (COVID-19) were explored. This study summarizes 195 clinical trials of advanced cell therapies targeting COVID-19 that were registered over the two years between January 2020 to December 2021. In addition, this work also analyzed the cell manufacturing and clinical delivery experience of 26 trials that published their outcomes by July 2022. Our demographic analysis found the highest number of cell therapy trials for COVID-19 was in United States, China, and Iran (N=53, 43, and 19, respectively), with the highest number per capita in Israel, Spain, Iran, Australia, and Sweden (N=0.641, 0.232, 0,223, 0.194, and 0.192 trials per million inhabitants). The leading cell types were multipotent mesenchymal stromal/stem cells (MSCs), natural killer (NK) cells, and mononuclear cells (MNCs), accounting for 72%, 9%, and 6% of the studies, respectively. There were 24 published clinical trials that reported on infusions of MSCs. A pooled analysis of these MSC studies found that MSCs provide a relative risk reduction for all-cause COVID-19 mortality of RR=0.63 (95% CI 0.46 to 0.85). This result corroborates previously published smaller meta-analyses, which suggested that MSC therapy demonstrated a clinical benefit for COVID-19 patients. The sources of the MSCs used in these studies and their manufacturing and clinical delivery methods were remarkably heterogeneous, with some predominance of perinatal tissue-derived products. Our results highlight the important role that cell therapy products may play as an adjunct therapy in the management of COVID-19 and its related complications, as well as the importance of controlling key manufacturing parameters to ensure comparability between studies. Thus, we support ongoing calls for a global registry of clinical studies with MSC products that could better link cell product manufacturing and delivery methods to clinical outcomes. Although advanced cell therapies may provide an important adjunct treatment for patients affected by COVID-19 in the near future, preventing pathology through vaccination still remains the best protection to date. We conducted a systematic review and meta-analysis of advanced cell therapy clinical trials as potential novel treatment for COVID-19 (resulting from SARS-CoV-2 coronavirus infection), including analysis of the global clinical trial landscape, published safety/efficacy outcomes (RR/OR), and details on cell product manufacturing and clinical delivery. This study had a 2-year observation interval from start of January 2020 to end of December 2021, including a follow-up period until end of July to identify published outcomes, which covers the most vivid period of clinical trial activity, and is also the longest observation period studied until today. In total, we identified 195 registered advanced cell therapy studies for COVID-19, employing 204 individual cell products. Leading registered trial activity was attributed to the USA, China, and Iran. Through the end of July 2022, 26 clinical trials were published, with 24 out of 26 articles employing intravenous infusions (IV) of mesenchymal stromal/stem cell (MSC) products. Most of the published trials were attributed to China and Iran. The cumulative results from the 24 published studies employing infusions of MSCs indicated an improved survival (RR=0.63 with 95% Confidence Interval 0.46 to 0.85). Our study is the most comprehensive systematic review and meta-analysis on cell therapy trials for COVID-19 conducted to date, clearly identifying the USA, China, and Iran as leading advanced cell therapy trial countries for COVID-19, with further strong contributions from Israel, Spain, Australia and Sweden. Although advanced cell therapies may provide an important adjunct treatment for patients affected by COVID-19 in the future, preventing pathology through vaccination remains the best protection.
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Affiliation(s)
- Pedro S. Couto
- Department of Biochemical Engineering, Advanced Centre for Biochemical Engineering, University College London, London, United Kingdom
- CellTrials.org and Parent’s Guide to Cord Blood Foundation, a non-profit organization headquartered in Brookeville, Brookeville, MD, United States
| | - Nada Al-Arawe
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health (BIH), Berlin, Germany
- Vascular Surgery Clinic, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Igor S. Filgueiras
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, SP, Brazil
| | - Dennyson L. M. Fonseca
- Interunit Postgraduate Program on Bioinformatics, Institute of Mathematics and Statistics (IME), University of São Paulo (USP), São Paulo, SP, Brazil
| | - Irene Hinterseher
- Vascular Surgery Clinic, Charité Universitätsmedizin Berlin, Berlin, Germany
- Department of Vascular Surgery, Universitätsklinikum Ruppin-Brandenburg, Medizinische Hochschule Brandenburg Theodor Fontane, Neuruppin, Germany
- Fakultät der Gesundheitswissenschaften Brandenburg, Gemeinsame Fakultät der Universität Potsdam, der Medizinischen Hochschule Brandenburg Theodor Fontane, und der Brandenburg Technischen Universität (BTU) Cottbus-Senftenberg, Potsdam, Germany
| | - Rusan A. Catar
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health (BIH), Berlin, Germany
| | - Raghavan Chinnadurai
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, United States
| | - Alexey Bersenev
- Advanced Cell Therapy (ACT) Laboratory, Yale School of Medicine, New Haven, CT, United States
| | - Otávio Cabral-Marques
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, SP, Brazil
- Interunit Postgraduate Program on Bioinformatics, Institute of Mathematics and Statistics (IME), University of São Paulo (USP), São Paulo, SP, Brazil
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo, SP, Brazil
- Department of Pharmacy and Postgraduate Program of Health and Science, Federal University of Rio Grande do Norte, Natal, Brazil
- Department of Medicine, Division of Molecular Medicine, University of São Paulo School of Medicine, São Paulo, Brazil
- Laboratory of Medical Investigation 29, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Guido Moll
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health (BIH), Berlin, Germany
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Frances Verter
- CellTrials.org and Parent’s Guide to Cord Blood Foundation, a non-profit organization headquartered in Brookeville, Brookeville, MD, United States
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24
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Chen W, Lv L, Chen N, Cui E. Immunogenicity of mesenchymal stromal/stem cells. Scand J Immunol 2023; 97:e13267. [PMID: 39007962 DOI: 10.1111/sji.13267] [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: 08/29/2022] [Revised: 03/06/2023] [Accepted: 03/17/2023] [Indexed: 04/07/2023]
Abstract
Mesenchymal stromal/stem cells (MSCs) possess the ability to self-renew and differentiate into other cell types. Because of their anti-inflammatory and immunomodulatory abilities, as well as their more ready availability compared to other stem cell sources, MSCs hold great promise for the treatment of many diseases, such as haematological defects, acute respiratory distress syndrome, autoimmunity, cardiovascular diseases, etc. However, immune rejection remains an important problem. MSCs are considered to have low immunogenicity, but they do not have full immunological privilege. This review analyzes and discusses the safety of MSCs from the perspective of their immunogenicity, with the aim of providing a reference for future research and clinical application.
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Affiliation(s)
- Wenyan Chen
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, 313000, Zhejiang, No. 1558, Third Ring North Road, Huzhou, China
| | - Lu Lv
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, 313000, Zhejiang, No. 1558, Third Ring North Road, Huzhou, China
| | - Na Chen
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, 313000, Zhejiang, No. 1558, Third Ring North Road, Huzhou, China
| | - Enhai Cui
- Department of Respiratory and Critical Care Medicine, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, 313000, Zhejiang, No. 1558, Third Ring North Road, Huzhou, China
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25
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Yan S, Campos de Souza S, Xie Z, Bao Y. Research progress in clinical trials of stem cell therapy for stroke and neurodegenerative diseases. IBRAIN 2023; 9:214-230. [PMID: 37786546 PMCID: PMC10529019 DOI: 10.1002/ibra.12095] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 02/14/2023] [Accepted: 02/16/2023] [Indexed: 10/04/2023]
Abstract
The incidence of stroke and neurodegenerative diseases is gradually increasing in modern society, but there is still no treatment that is effective enough. Stem cells are cells that can reproduce (self-renew) and differentiate into the body, which have shown significance in basic research, while doctors have also taken them into clinical trials to determine their efficacy and safety. Existing clinical trials mainly include middle-aged and elderly patients with stroke or Parkinson's disease (mostly 40-80 years old), mainly involving injection of mesenchymal stem cells and bone marrow mesenchymal stem cells through the veins and the putamen, with a dosage of mostly 106-108 cells. The neural and motor functions of the patients were restored after stem cell therapy, and the safety was found to be good during the follow-up period of 3 months to 5 years. Here, we review all clinical trials and the latest advances in stroke, Alzheimer's disease, and Parkinson's disease, with the hope that stem cell therapy will be used in the clinic in the future to achieve effective treatment rates and benefit patients.
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Affiliation(s)
- Shan‐Shan Yan
- Department of AnesthesiologySouthwest Medical UniversityLuzhouChina
| | - Senio Campos de Souza
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical SciencesUniversity of MacauMacau SARChina
| | - Zhen‐Dong Xie
- Institute for Bioengineering of CataloniaUniversity of BarcelonaCarrer de Baldiri ReixacBarcelonaSpain
| | - Yong‐Xin Bao
- Qingdao Women and Children's HospitalQingdao UniversityQingdaoChina
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26
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Chinnadurai R, Viswanathan S, Moll G. Editorial: Next generation MSC therapy manufacturing, potency and mechanism of action analysis. Front Immunol 2023; 14:1192636. [PMID: 37153609 PMCID: PMC10161792 DOI: 10.3389/fimmu.2023.1192636] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 04/04/2023] [Indexed: 05/09/2023] Open
Affiliation(s)
- Raghavan Chinnadurai
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, United States
- *Correspondence: Raghavan Chinnadurai, ; Sowmya Viswanathan, ; Guido Moll,
| | - Sowmya Viswanathan
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada
- Krembil Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Biomedical Engineering, Division of Hematology, Department of Medicine, University of Toronto, Toronto, ON, Canada
- *Correspondence: Raghavan Chinnadurai, ; Sowmya Viswanathan, ; Guido Moll,
| | - Guido Moll
- BIH Center for Regenerative Therapies (BCRT), Berlin, Germany
- Berlin-Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany
- Department of Nephrology and Internal Intensive Care Medicine, all Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health (BIH), Berlin, Germany
- *Correspondence: Raghavan Chinnadurai, ; Sowmya Viswanathan, ; Guido Moll,
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Lau H, Han DW, Park J, Lehner E, Kals C, Arzt C, Bayer E, Auer D, Schally T, Grasmann E, Fang H, Lee J, Lee HS, Han J, Gimona M, Rohde E, Bae S, Oh SW. GMP-compliant manufacturing of biologically active cell-derived vesicles produced by extrusion technology. JOURNAL OF EXTRACELLULAR BIOLOGY 2022; 1:e70. [PMID: 38938599 PMCID: PMC11080851 DOI: 10.1002/jex2.70] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 10/08/2022] [Accepted: 11/01/2022] [Indexed: 06/29/2024]
Abstract
Extracellular vesicles (EVs) released by a variety of cell types have been shown to act as a natural delivery system for bioactive molecules such as RNAs and proteins. EV therapy holds great promise as a safe and cell-free therapy for many immunological and degenerative diseases. However, translation to clinical application is limited by several factors, including insufficient large-scale manufacturing technologies and low yield. We have developed a novel drug delivery platform technology, BioDrone™, based on cell-derived vesicles (CDVs) produced from diverse cell sources by using a proprietary extrusion process. This extrusion technology generates nanosized vesicles in far greater numbers than naturally obtained EVs. We demonstrate that the CDVs are surrounded by a lipid bilayer membrane with a correct membrane topology. Physical, biochemical and functional characterisation results demonstrate the potential of CDVs to act as effective therapeutics. Umbilical cord mesenchymal stem cell (UCMSC)-derived CDVs exhibit a biological activity that is similar to UCMSCs or UCMSC-derived EVs. Lastly, we present the establishment of a GMP-compliant process to allow the production of a large number of UCMSC-CDVs in a reproducible manner. GMP-compliant manufacturing of CDVs will facilitate the preclinical and clinical evaluation of these emerging therapeutics in anti-inflammatory or regenerative medicine. This study also represents a crucial step in the development of this novel drug delivery platform based on CDVs.
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Affiliation(s)
| | - Dong Woo Han
- BioDrone Research InstituteMDimune Inc.SeoulKorea
| | - Jinhee Park
- BioDrone Research InstituteMDimune Inc.SeoulKorea
| | - Edwine Lehner
- GMP Unit, Spinal Cord Injury & Tissue Regeneration Centre Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
| | - Carina Kals
- GMP Unit, Spinal Cord Injury & Tissue Regeneration Centre Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
| | - Claudia Arzt
- Transfer Centre for Extracellular Vesicle Theralytic Technologies (EV‐TT)SalzburgAustria
| | - Elisabeth Bayer
- GMP Unit, Spinal Cord Injury & Tissue Regeneration Centre Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
| | - Daniela Auer
- GMP Unit, Spinal Cord Injury & Tissue Regeneration Centre Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
| | - Tanja Schally
- GMP Unit, Spinal Cord Injury & Tissue Regeneration Centre Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
| | - Eva Grasmann
- Transfer Centre for Extracellular Vesicle Theralytic Technologies (EV‐TT)SalzburgAustria
| | - Han Fang
- Transfer Centre for Extracellular Vesicle Theralytic Technologies (EV‐TT)SalzburgAustria
| | - Jae‐Young Lee
- Department of Ophthalmology, Eunpyeong St. Mary's Hospital, College of MedicineThe Catholic University of KoreaSeoulKorea
| | - Hyun Soo Lee
- Department of Ophthalmology, Eunpyeong St. Mary's Hospital, College of MedicineThe Catholic University of KoreaSeoulKorea
| | - Jinah Han
- BioDrone Therapeutics Inc.SeattleUSA
| | - Mario Gimona
- GMP Unit, Spinal Cord Injury & Tissue Regeneration Centre Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
- Transfer Centre for Extracellular Vesicle Theralytic Technologies (EV‐TT)SalzburgAustria
- Research Program “Nanovesicular Therapies”Paracelsus Medical UniversitySalzburgAustria
| | - Eva Rohde
- GMP Unit, Spinal Cord Injury & Tissue Regeneration Centre Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
- Department of Transfusion Medicine, University HospitalSalzburger Landeskliniken GesmbH (SALK) and Paracelsus Medical UniversitySalzburgAustria
| | - Shingyu Bae
- BioDrone Research InstituteMDimune Inc.SeoulKorea
| | - Seung Wook Oh
- BioDrone Research InstituteMDimune Inc.SeoulKorea
- BioDrone Therapeutics Inc.SeattleUSA
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Baranovskii DS, Klabukov ID, Arguchinskaya NV, Yakimova AO, Kisel AA, Yatsenko EM, Ivanov SA, Shegay PV, Kaprin AD. Adverse events, side effects and complications in mesenchymal stromal cell-based therapies. Stem Cell Investig 2022; 9:7. [PMID: 36393919 PMCID: PMC9659480 DOI: 10.21037/sci-2022-025] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 10/28/2022] [Indexed: 07/22/2023]
Abstract
Numerous clinical studies have shown a wide clinical potential of mesenchymal stromal cells (MSCs) application. However, recent experience has accumulated numerous reports of adverse events and side effects associated with MSCs therapy. Furthermore, the strategies and methods of MSCs therapy did not change significantly in recent decades despite the clinical impact and awareness of potential complications. An extended understanding of limitations could lead to a wider clinical implementation of safe cell therapies and avoid harmful approaches. Therefore, our objective was to summarize the possible negative effects observed during MSCs-based therapies. We were also aimed to discuss the risks caused by weaknesses in cell processing, including isolation, culturing, and storage. Cell processing and cell culture could dramatically influence cell population profile, change protein expression and cell differentiation paving the way for future negative effects. Long-term cell culture led to accumulation of chromosomal abnormalities. Overdosed antibiotics in culture media enhanced the risk of mycoplasma contamination. Clinical trials reported thromboembolism and fibrosis as the most common adverse events of MSCs therapy. Their delayed manifestation generally depends on the patient's individual phenotype and requires specific awareness during the clinical trials with obligatory inclusion in the patient' informed consents. Finally we prepared the safety checklist, recommended for clinical specialists before administration or planning of MSCs therapy.
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Affiliation(s)
- Denis S. Baranovskii
- National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Obninsk, Russia
- Peoples’ Friendship University of Russia (RUDN University), Moscow, Russia
| | - Ilya D. Klabukov
- National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Obninsk, Russia
- Peoples’ Friendship University of Russia (RUDN University), Moscow, Russia
- Obninsk Institute for Nuclear Power Engineering of the National Research Nuclear University MEPhI, Obninsk, Russia
| | - Nadezhda V. Arguchinskaya
- National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Obninsk, Russia
| | - Anna O. Yakimova
- National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Obninsk, Russia
| | - Anastas A. Kisel
- National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Obninsk, Russia
| | - Elena M. Yatsenko
- National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Obninsk, Russia
| | - Sergei A. Ivanov
- National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Obninsk, Russia
| | - Peter V. Shegay
- National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Obninsk, Russia
| | - Andrey D. Kaprin
- National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Obninsk, Russia
- Peoples’ Friendship University of Russia (RUDN University), Moscow, Russia
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29
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Jenssen AB, Mohamed-Ahmed S, Kankuri E, Brekke RL, Guttormsen AB, Gjertsen BT, Mustafa K, Almeland SK. Administration Methods of Mesenchymal Stem Cells in the Treatment of Burn Wounds. EUROPEAN BURN JOURNAL 2022; 3:493-516. [PMID: 39600017 PMCID: PMC11571831 DOI: 10.3390/ebj3040043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 10/28/2022] [Accepted: 11/01/2022] [Indexed: 11/29/2024]
Abstract
Cellular therapies for burn wound healing, including the administration of mesenchymal stem or stromal cells (MSCs), have shown promising results. This review aims to provide an overview of the current administration methods in preclinical and clinical studies of bone-marrow-, adipose-tissue-, and umbilical-cord-derived MSCs for treating burn wounds. Relevant studies were identified through a literature search in PubMed and Embase and subjected to inclusion and exclusion criteria for eligibility. Additional relevant studies were identified through a manual search of reference lists. A total of sixty-nine studies were included in this review. Of the included studies, only five had clinical data from patients, one was a prospective case-control, three were case reports, and one was a case series. Administration methods used were local injection (41% in preclinical and 40% in clinical studies), cell-seeded scaffolds (35% and 20%), topical application (17% and 60%), and systemic injection (1% and 0%). There was great heterogeneity between the studies regarding experimental models, administration methods, and cell dosages. Local injection was the most common administration method in animal studies, while topical application was used in most clinical reports. The best delivery method of MSCs in burn wounds is yet to be identified. Although the potential of MSC treatment for burn wounds is promising, future research should focus on examining the effect and scalability of such therapy in clinical trials.
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Affiliation(s)
- Astrid Bjørke Jenssen
- Norwegian National Burn Center, Department of Plastic, Hand, and Reconstructive Surgery, Haukeland University Hospital, 5021 Bergen, Norway
| | - Samih Mohamed-Ahmed
- Center for Translational Oral Research (TOR), Tissue Engineering Group, Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, 5020 Bergen, Norway
| | - Esko Kankuri
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland
| | - Ragnvald Ljones Brekke
- Norwegian National Burn Center, Department of Plastic, Hand, and Reconstructive Surgery, Haukeland University Hospital, 5021 Bergen, Norway
- Department of Clinical Medicine, Faculty of Medicine, University of Bergen, 5020 Bergen, Norway
| | - Anne Berit Guttormsen
- Department of Clinical Medicine, Faculty of Medicine, University of Bergen, 5020 Bergen, Norway
- Department of Anesthesia and Intensive Care, Haukeland University Hospital, 5021 Bergen, Norway
| | - Bjørn Tore Gjertsen
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway
- Department of Medicine, Hematology Section, Haukeland University Hospital, 5021 Bergen, Norway
| | - Kamal Mustafa
- Center for Translational Oral Research (TOR), Tissue Engineering Group, Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, 5020 Bergen, Norway
| | - Stian Kreken Almeland
- Norwegian National Burn Center, Department of Plastic, Hand, and Reconstructive Surgery, Haukeland University Hospital, 5021 Bergen, Norway
- Department of Clinical Medicine, Faculty of Medicine, University of Bergen, 5020 Bergen, Norway
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30
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Wang Y, Fang J, Liu B, Shao C, Shi Y. Reciprocal regulation of mesenchymal stem cells and immune responses. Cell Stem Cell 2022; 29:1515-1530. [DOI: 10.1016/j.stem.2022.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/19/2022] [Accepted: 10/04/2022] [Indexed: 11/06/2022]
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31
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Shirbaghaee Z, Hassani M, Heidari Keshel S, Soleimani M. Emerging roles of mesenchymal stem cell therapy in patients with critical limb ischemia. Stem Cell Res Ther 2022; 13:462. [PMID: 36068595 PMCID: PMC9449296 DOI: 10.1186/s13287-022-03148-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/19/2022] [Indexed: 11/25/2022] Open
Abstract
Critical limb ischemia (CLI), the terminal stage of peripheral arterial disease (PAD), is characterized by an extremely high risk of amputation and vascular issues, resulting in severe morbidity and mortality. In patients with severe limb ischemia with no alternative therapy options, such as endovascular angioplasty or bypass surgery, therapeutic angiogenesis utilizing cell-based therapies is vital for increasing blood flow to ischemic regions. Mesenchymal stem cells (MSCs) are currently considered one of the most encouraging cells as a regenerative alternative for the surgical treatment of CLI, including restoring tissue function and repairing ischemic tissue via immunomodulation and angiogenesis. The regenerative treatments for limb ischemia based on MSC therapy are still considered experimental. Despite recent advances in preclinical and clinical research studies, it is not recommended for regular clinical use. In this study, we review the immunomodulatory features of MSC besides the current understanding of different sources of MSC in the angiogenic treatment of CLI subjects and their potential applications as therapeutic agents. Specifically, this paper concentrates on the most current clinical application issues, and several recommendations are provided to improve the efficacy of cell therapy for CLI patients.
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Affiliation(s)
- Zeinab Shirbaghaee
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hassani
- Department of Vascular and Endovascular Surgery, Ayatollah Taleghani Hospital Research Development Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Heidari Keshel
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoud Soleimani
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. .,Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. .,Applied Cell Science and Hematology Department, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran.
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32
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Upadhyay TK, Trivedi R, Khan F, Pandey P, Sharangi AB, Goel H, Saeed M, Park MN, Kim B. Potential Therapeutic Role of Mesenchymal-Derived Stem Cells as an Alternative Therapy to Combat COVID-19 through Cytokines Storm. Cells 2022; 11:2686. [PMID: 36078094 PMCID: PMC9455060 DOI: 10.3390/cells11172686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 08/20/2022] [Accepted: 08/25/2022] [Indexed: 01/08/2023] Open
Abstract
Medical health systems continue to be challenged due to newly emerging COVID-19, and there is an urgent need for alternative approaches for treatment. An increasing number of clinical observations indicate cytokine storms to be associated with COVID-19 severity and also to be a significant cause of death among COVID-19 patients. Cytokine storm involves the extensive proliferative and hyperactive activity of T and macrophage cells and the overproduction of pro-inflammatory cytokines. Stem cells are the type of cell having self-renewal properties and giving rise to differentiated cells. Currently, stem cell therapy is an exciting and promising therapeutic approach that can treat several diseases that were considered incurable in the past. It may be possible to develop novel methods to treat various diseases by identifying stem cells' growth and differentiation factors. Treatment with mesenchymal stem cells (MSCs) in medicine is anticipated to be highly effective. The present review article is organized to put forward the positive arguments and implications in support of mesenchymal stem cell therapy as an alternative therapy to cytokine storms, to combat COVID-19. Using the immunomodulatory potential of the MSCs, it is possible to fight against COVID-19 and counterbalance the cytokine storm.
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Affiliation(s)
- Tarun Kumar Upadhyay
- Department of Biotechnology, Parul Institute of Applied Sciences and Animal Cell Culture and Immunobiochemistry Lab, Centre of Research for Development, Parul University, Vadodara 391760, India
| | - Rashmi Trivedi
- Department of Biotechnology, Parul Institute of Applied Sciences and Animal Cell Culture and Immunobiochemistry Lab, Centre of Research for Development, Parul University, Vadodara 391760, India
| | - Fahad Khan
- Department of Biotechnology, Noida Institute of Engineering & Technology, Greater Noida 201306, India
| | - Pratibha Pandey
- Department of Biotechnology, Noida Institute of Engineering & Technology, Greater Noida 201306, India
| | - Amit Baran Sharangi
- Department of Plantation, Spices, Medicinal & Aromatic Crops, BCKV-Agricultural University, Mohanpur 741252, India
| | - Harsh Goel
- Department of Laboratory Oncology, All India Institute of Medical Sciences, New Delhi 110023, India
| | - Mohd Saeed
- Department of Biology, College of Sciences, University of Hail, Hail 34464, Saudi Arabia
| | - Moon Nyeo Park
- Department of Korean Medicine, Kyung Hee University, Seoul 05254, Korea
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
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33
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Owen A, Patten D, Vigneswara V, Frampton J, Newsome PN. PDGFRα/Sca-1 Sorted Mesenchymal Stromal Cells Reduce Liver Injury in Murine Models of Hepatic Ischemia-Reperfusion Injury. Stem Cells 2022; 40:1056-1070. [PMID: 35999023 PMCID: PMC9707286 DOI: 10.1093/stmcls/sxac059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 07/06/2022] [Indexed: 11/12/2022]
Abstract
Liver transplantation is an effective therapy, but increasing demand for donor organs has led to the use of marginal donor organs with increased complication rates. Mesenchymal stromal cells (MSC) pleiotropically modulate aberrant immune-mediated responses and represent a potential therapy to target the inflammation seen post-transplant with marginal donor livers. To avoid the confounding effects of xenotransplantation seen in studies with human MSC, a PDGFRα/Sca-1 (PaS) sorted MSC population was used which was analogous to human MSC populations (LNGFR+Thy-1+VCAM-1Hi). PaS MSC are a well-described population that demonstrate MSC properties without evidence of clonal mutation during expansion. We demonstrate their anti-inflammatory properties herein through their suppression of T-lymphocyte proliferation in vitro and secretion of anti-inflammatory cytokines (IL-10 and OPG) after stimulation (P = .004 and P = .003). The MDR2-/- model of biliary injury and hepatic ischemia-reperfusion (HIR) injury models were used to replicate the non-anastomotic biliary complications seen following liver transplantation. Systemic MSC therapy in MDR2-/- mice led to reduced liver injury with an increase in restorative macrophages (5913 ± 333.9 vs 12 597 ± 665.8, P = .002, n = 7) and a change in lymphocyte ratios (3.55 ± 0.37 vs 2.59 ± 0.139, P = .023, n = 17), whereas subcutaneous administration of MSC showed no beneficial effect. MSC also reduced cell death in the HIR model assessed by Periodic acid-Schiff (PAS) staining (91.7% ± 2.8 vs 80.1% ± 4.6, P = .03). Systemically administered quantum dot-labeled MSC were tracked using single-cell resolution CryoViz imaging which demonstrated their sequestration in the lungs alongside retention/redistribution to injured liver tissue. MSC represent a potential novel therapy in marginal organ transplantation which warrants further study.
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Affiliation(s)
| | | | | | | | - Philip N Newsome
- Corresponding author: Philip N. Newsome, Centre for Liver and Gastrointestinal Research, Institute of Biomedical Research, University of Birmingham, Vincent Drive, Birmingham B15 2TT, UK.
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Eiro N, Fraile M, González-Jubete A, González LO, Vizoso FJ. Mesenchymal (Stem) Stromal Cells Based as New Therapeutic Alternative in Inflammatory Bowel Disease: Basic Mechanisms, Experimental and Clinical Evidence, and Challenges. Int J Mol Sci 2022; 23:ijms23168905. [PMID: 36012170 PMCID: PMC9408403 DOI: 10.3390/ijms23168905] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 07/26/2022] [Accepted: 07/26/2022] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are an example of chronic diseases affecting 40% of the population, which involved tissue damage and an inflammatory process not satisfactorily controlled with current therapies. Data suggest that mesenchymal stem cells (MSC) may be a therapeutic option for these processes, and especially for IBD, due to their multifactorial approaches such as anti-inflammatory, anti-oxidative stress, anti-apoptotic, anti-fibrotic, regenerative, angiogenic, anti-tumor, or anti-microbial. However, MSC therapy is associated with important limitations as safety issues, handling difficulties for therapeutic purposes, and high economic cost. MSC-derived secretome products (conditioned medium or extracellular vesicles) are therefore a therapeutic option in IBD as they exhibit similar effects to their parent cells and avoid the issues of cell therapy. In this review, we proposed further studies to choose the ideal tissue source of MSC to treat IBD, the implementation of new standardized production strategies, quality controls and the integration of other technologies, such as hydrogels, which may improve the therapeutic effects of derived-MSC secretome products in IBD.
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Affiliation(s)
- Noemi Eiro
- Research Unit, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
- Correspondence: (N.E.); (F.J.V.); Tel.: +34-98-5320050 (ext. 84216) (N.E.); Fax: +34-98-531570 (N.E.)
| | - Maria Fraile
- Research Unit, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
| | | | - Luis O. González
- Department of Anatomical Pathology, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
| | - Francisco J. Vizoso
- Research Unit, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
- Department of Surgery, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
- Correspondence: (N.E.); (F.J.V.); Tel.: +34-98-5320050 (ext. 84216) (N.E.); Fax: +34-98-531570 (N.E.)
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35
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Moonshi SS, Adelnia H, Wu Y, Ta HT. Placenta‐Derived Mesenchymal Stem Cells for Treatment of Diseases: A Clinically Relevant Source. ADVANCED THERAPEUTICS 2022. [DOI: 10.1002/adtp.202200054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Shehzahdi S. Moonshi
- Queensland Micro‐ and Nanotechnology Centre Griffith University Nathan Queensland 4111 Australia
| | - Hossein Adelnia
- Queensland Micro‐ and Nanotechnology Centre Griffith University Nathan Queensland 4111 Australia
- Australian Institute for Bioengineering and Nanotechnology University of Queensland St Lucia Queensland 4072 Australia
| | - Yuao Wu
- Queensland Micro‐ and Nanotechnology Centre Griffith University Nathan Queensland 4111 Australia
| | - Hang T. Ta
- Queensland Micro‐ and Nanotechnology Centre Griffith University Nathan Queensland 4111 Australia
- Bioscience Discipline School of Environment and Science Griffith University Nathan Queensland 4111 Australia
- Australian Institute for Bioengineering and Nanotechnology University of Queensland St Lucia Queensland 4072 Australia
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36
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Zhang M, Yan X, Shi M, Li R, Pi Z, Ren X, Wang Y, Yan S, Wang Y, Jin Y, Wang X. Safety and efficiency of stem cell therapy for COVID-19: a systematic review and meta-analysis. Glob Health Res Policy 2022; 7:19. [PMID: 35733229 PMCID: PMC9217728 DOI: 10.1186/s41256-022-00251-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 05/31/2022] [Indexed: 11/13/2022] Open
Abstract
Background With the COVID-19 pandemic continuing, various treatments have become widely practiced. Stem cells have a wide range of applications in the treatment of lung diseases and have therefore been experimentally used to treat patients with COVID-19, but whether the expanded use of stem cells is safe and reliable still lacks enough evidence. To address this issue, we systematically reviewed the safety and efficiency of stem cell therapy in COVID-19 cases. Methods We searched PubMed, Embase, Web of Science, The Cochrane Library, CNKI, WanFang, VIP and SinoMed up to January 18, 2022. The included studies were assessed using the Risk-of-bias tool 1.0 and MINORS instrument. The adverse events, mortality, length of hospital day and laboratory parameters were analyzed by meta-analysis. We adhered to PRISMA reporting guideline. Results We have included 17 studies meeting the inclusion data. There were no significant differences in AEs (OR = 0·39, 95% CI = 0·12 to 1·33, P = 0·13, I2 = 58%) and SAEs (OR = 0·21, 95% CI = 0·04 to 1·03, P = 0·05, I2 = 0%) between stem cell therapy group and control group. The analysis showed that stem cell treatment could significantly reduce the mortality rate(OR = 0·24, 95% CI = 0·13 to 0·45, P < 0·01, I2 = 0%), but was not able to cause changes in length of hospital stay or most laboratory parameters. Conclusions The present study shows that stem cell therapy for COVID-19 has a remarkable effect on efficiency without increasing risks of adverse events and length of hospital stay. It is potentially necessary to establish the criteria for COVID-19 for stem cell therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s41256-022-00251-5.
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Affiliation(s)
- Minghe Zhang
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Xinchun Yan
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Minghui Shi
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Ruihang Li
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Ziwei Pi
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.,Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Xiangying Ren
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Yongbo Wang
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Siyu Yan
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Yunyun Wang
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Yinghui Jin
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Xinghuan Wang
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China. .,Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
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37
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Li X, Huang Q, Zhang X, Xie C, Liu M, Yuan Y, Feng J, Xing H, Ru L, Yuan Z, Xu Z, Yang Y, Long Y, Xing C, Song J, Hu X, Xu Q. Reproductive and Developmental Toxicity Assessment of Human Umbilical Cord Mesenchymal Stem Cells in Rats. Front Cell Dev Biol 2022; 10:883996. [PMID: 35663387 PMCID: PMC9160830 DOI: 10.3389/fcell.2022.883996] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 03/28/2022] [Indexed: 11/13/2022] Open
Abstract
Objective: Human umbilical cord mesenchymal stem cells (hUC-MSCs) have shown very attractive potential in clinical applications for the treatment of various diseases. However, the data about the reproductive and developmental toxicity of hUC-MSCs remains insufficient. Thus, we assessed the potential effects of intravenous injection of hUC-MSCs on reproduction and development in Sprague-Dawley rats. Methods: In the fertility and early embryonic development study, hUC-MSCs were administered at dose levels of 0, 6.0 × 106, 8.5 × 106, and 1.2 × 107/kg to male and female rats during the pre-mating, mating and gestation period. In the embryo-fetal development study, the pregnant female rats received 0, 6.0 × 106, 1.2 × 107, and 2.4 × 107/kg of hUC-MSCs from gestation days (GD) 6-15. Assessments made included mortality, clinical observations, body weight, food consumption, fertility parameters of male and female, litter, and fetus parameters, etc. Results: No hUC-MSCs-related toxicity was observed on the fertility of male and female rats, and no teratogenic effect on fetuses. hUC-MSCs at 1.2 × 107/kg caused a mildly decrease in body weight gain of male rats, transient listlessness, tachypnea, and hematuria symptoms in pregnant female rats. Death was observed in part of the pregnant females at a dose of 2.4 × 107/kg, which could be due to pulmonary embolism. Conclusion: Based on the results of the studies, the no-observed-adverse-effect levels (NOAELs) are 8.5 × 106/kg for fertility and early embryonic development, 1.2 × 107/kg for maternal toxicity and 2.4 × 107/kg for embryo-fetal development in rats intravenous injected with hUC-MSCs, which are equivalent to 8.5-fold, 12-fold, and 24-fold respectively of its clinical dosage in humans. These findings may provide a rational basis for human health risk assessment of hUC-MSCs.
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Affiliation(s)
- Xiaobo Li
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Country Sci-Tech Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qijing Huang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiangxiang Zhang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Changfeng Xie
- Shenzhen Beike Biotechnology Co., Ltd., Shenzhen, China
| | - Muyun Liu
- Shenzhen Beike Biotechnology Co., Ltd., Shenzhen, China
| | - Yueming Yuan
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Country Sci-Tech Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jianjia Feng
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Haoyu Xing
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Li Ru
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Country Sci-Tech Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zheng Yuan
- Country Sci-Tech Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhiyong Xu
- Country Sci-Tech Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - YaoXiang Yang
- Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Yan Long
- Guangzhou Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou, China
| | - Chengfeng Xing
- Country Sci-Tech Industrial Park, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jianping Song
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiang Hu
- Shenzhen Beike Biotechnology Co., Ltd., Shenzhen, China
| | - Qin Xu
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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Yeo-Teh NSL, Tang BL. Moral obligations in conducting stem cell-based therapy trials for autism spectrum disorder. JOURNAL OF MEDICAL ETHICS 2022; 48:343-348. [PMID: 33858947 DOI: 10.1136/medethics-2020-107106] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 03/04/2021] [Accepted: 03/20/2021] [Indexed: 06/12/2023]
Abstract
Unregulated patient treatments and approved clinical trials have been conducted with haematopoietic stem cells and mesenchymal stem cells for children with autism spectrum disorder (ASD). While the former direct-to-consumer practice is usually considered rogue and should be legally constrained, regulated clinical trials could also be ethically questionable. Here, we outline principal objections against these trials as they are currently conducted. Notably, these often lack a clear rationale for how transplanted cells may confer a therapeutic benefit in ASD, and thus, have ill-defined therapeutic outcomes. We posit that ambiguous and unsubstantiated descriptions of outcome from such clinical trials may nonetheless appeal to the lay public as being based on authentic scientific findings. These may further fuel caregivers of patients with ASD to pursue unregulated direct-to-consumer treatments, thus exposing them to unnecessary risks. There is, therefore, a moral obligation on the part of those regulating and conducting clinical trials of stem cell-based therapeutic for ASD minors to incorporate clear therapeutic targets, scientific rigour and reporting accuracy in their work. Any further stem cell-based trials for ASD unsupported by significant preclinical advances and particularly sound scientific hypothesis and aims would be ethically indefensible.
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Affiliation(s)
| | - Bor Luen Tang
- Research Compliance and Integrity Office, National University of Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore
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Araldi RP, Prezoto BC, Gonzaga V, Policiquio B, Mendes TB, D’Amélio F, Vigerelli H, Viana M, Valverde CW, Pagani E, Kerkis I. Advanced cell therapy with low tissue factor loaded product NestaCell® does not confer thrombogenic risk for critically ill COVID-19 heparin-treated patients. Pharmacotherapy 2022; 149:112920. [PMID: 36068779 PMCID: PMC8971080 DOI: 10.1016/j.biopha.2022.112920] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/26/2022] [Accepted: 03/30/2022] [Indexed: 12/15/2022]
Abstract
Since the COVID-19 pandemic started, mesenchymal stromal cells (MSC) appeared as a therapeutic option to reduce the over-activated inflammatory response and promote recovery of lung damage. Most clinical studies use intravenous injection for MSC delivery, raising several concerns of thrombogenic risk due to MSC procoagulant activity (PCA) linked to the expression of tissue factor (TF/CD142). This is the first study that demonstrated procoagulant activity of TF+ human immature dental pulp stromal cells (hIDPSC, NestaCell® product) with the percentage of TF+ cells varied from 0.2% to 63.9% in plasma of healthy donors and COVID-19 heparin-treated patients. Thrombogenic risk of TF+ hIDPSCs was evaluated by rotational thromboelastometry (in vitro) and in critically ill COVID-19 patients (clinical trial). We showed that the thromboelastography is not enough to predict the risk of TF+ MSC therapies. Using TF-negative HUVEC cells, we demonstrated that TF is not a unique factor responsible for the cell's procoagulant activity. However, heparin treatment minimizes MSC procoagulant (in vitro). We also showed that the intravenous infusion of hIDPSCs with prophylactic enoxaparin administration in moderate to critically ill COVID-19 patients did not change the values of D-dimer, neither in the PT and PTT times. Our COVID-19 clinical study measured and selected the therapeutic cells with low TF (less than 25% of TF+ hIDPSCs). Our data indicate that the concomitant administration of enoxaparin and low TF-loaded is safe even for critically ill COVID-19 patients.
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40
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Ringdén O, Moll G, Gustafsson B, Sadeghi B. Mesenchymal Stromal Cells for Enhancing Hematopoietic Engraftment and Treatment of Graft-Versus-Host Disease, Hemorrhages and Acute Respiratory Distress Syndrome. Front Immunol 2022; 13:839844. [PMID: 35371003 PMCID: PMC8973075 DOI: 10.3389/fimmu.2022.839844] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/17/2022] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) possess profound immunomodulatory and regenerative properties that are of clinical use in numerous clinical indications with unmet medical need. Common sources of MSCs include among others, bone marrow (BM), fat, umbilical cord, and placenta-derived decidua stromal cells (DSCs). We here summarize our more than 20-years of scientific experience in the clinical use of MSCs and DSCs in different clinical settings. BM-MSCs were first explored to enhance the engraftment of autografts in hematopoietic cell transplantation (HCT) and osteogenesis imperfecta around 30 years ago. In 2004, our group reported the first anti-inflammatory use of BM-MSCs in a child with grade IV acute graft-versus-host disease (GvHD). Subsequent studies have shown that MSCs appear to be more effective in acute than chronic GvHD. Today BM-MSC-therapy is registered for acute GvHD in Japan and for GvHD in children in Canada and New Zeeland. MSCs first home to the lung following intravenous injection and exert strong local and systemic immunomodulatory effects on the host immune system. Thus, they were studied for ameliorating the cytokine storm in acute respiratory distress syndrome (ARDS). Both, MSCs and DSCs were used to treat SARS-CoV-2 coronavirus-induced disease 2019 (COVID-19)-induced ARDS. In addition, they were also used for other novel indications, such as pneumomediastinum, colon perforation, and radiculomyelopathy. MSC and DSCs trigger coagulation and were thus explored to stop hemorrhages. DSCs appear to be more effective for acute GvHD, ARDS, and hemorrhages, but randomized studies are needed to prove superiority. Stromal cell infusion is safe, well tolerated, and only gives rise to a slight fever in a limited number of patients, but no major side effects have been reported in multiple safety studies and metaanalysis. In this review we summarize current evidence from in vitro studies, animal models, and importantly our clinical experience, to support stromal cell therapy in multiple clinical indications. This encloses MSC's effects on the immune system, coagulation, and their safety and efficacy, which are discussed in relation to prominent clinical trials within the field.
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Affiliation(s)
- Olle Ringdén
- Translational Cell Therapy Research Group, Department of Clinical Sciences, Intervention and Technology (CLNTEC), Division of Pediatrics, Karolinska Institutet, Stockholm, Sweden
| | - Guido Moll
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT) and Berlin-Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany
- Department of Nephrology and Internal Intensive Care Medicine, All Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Britt Gustafsson
- Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
| | - Behnam Sadeghi
- Translational Cell Therapy Research Group, Department of Clinical Sciences, Intervention and Technology (CLNTEC), Division of Pediatrics, Karolinska Institutet, Stockholm, Sweden
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41
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Gilkeson GS. Safety and Efficacy of Mesenchymal Stromal Cells and Other Cellular Therapeutics in Rheumatic Diseases in 2022: A review of what we know so far. Arthritis Rheumatol 2022; 74:752-765. [PMID: 35128813 DOI: 10.1002/art.42081] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 12/13/2021] [Accepted: 02/01/2022] [Indexed: 11/06/2022]
Abstract
Although there are a number of new immunosuppressives and biologics approved for treating various autoimmune/inflammatory rheumatic diseases, there remain a substantial number of patients who have no clinical response or limited clinical response to these available treatments. Use of cellular therapies is a novel approach for the treatment of autoimmune/inflammatory rheumatic diseases with perhaps enhanced efficacy and less toxicity than current therapies. Autologous hematopoietic stem cell transplants were the first foray into cellular therapies with proven efficacy in scleroderma and multiple sclerosis. Newer yet unproven cellular therapies include allogenic mesenchymal stromal cells, shown effective in graft vs host disease and in healing of Crohn's fistulas. CAR-T cells are effective in various malignancies with possible usage in rheumatic diseases, as shown in preclinical studies in murine lupus and recently in human lupus. T regulatory cells are one of the master controllers of the immune response and are decreased in number and/or effectiveness in specific autoimmune diseases. Expansion of autologous T regulatory cells is an attractive approach to controlling autoimmunity. There are a number of other regulatory cells in the immune system including regulatory B cells, dendritic cells, macrophages, and other T cell types that are early in development. In this review, the current evidence for efficacy and mechanisms of actions of cellular therapies already in use or in clinical trials in human autoimmune diseases will be discussed including limitations of these therapies and potential side effects.
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Affiliation(s)
- Gary S Gilkeson
- Department of Medicine, Medical University of South Carolina, Charleston, SC.,Medical Research Service, Ralph H. Johnson VAMC, Charleston, SC
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42
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González-González A, García-Sánchez D, Alfonso-Fernández A, Haider KH, Rodríguez-Rey JC, Pérez-Campo FM. Regenerative Medicine Applied to the Treatment of Musculoskeletal Pathologies. HANDBOOK OF STEM CELL THERAPY 2022:1123-1158. [DOI: 10.1007/978-981-19-2655-6_50] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Moll G, Ankrum JA, Olson SD, Nolta JA. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:2-13. [PMID: 35641163 PMCID: PMC8895495 DOI: 10.1093/stcltm/szab005] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 09/27/2021] [Indexed: 11/22/2022] Open
Abstract
The number of mesenchymal stromal/stem cell (MSC) therapeutics and types of clinical applications have greatly diversified during the past decade, including rapid growth of poorly regulated “Stem Cell Clinics” offering diverse “Unproven Stem Cell Interventions.” This product diversification necessitates a critical evaluation of the reliance on the 2006 MSC minimal criteria to not only define MSC identity but characterize MSC suitability for intravascular administration. While high-quality MSC therapeutics have been safely administered intravascularly in well-controlled clinical trials, repeated case reports of mild-to-more-severe adverse events have been reported. These are most commonly related to thromboembolic complications upon infusion of highly procoagulant tissue factor (TF/CD142)-expressing MSC products. As TF/CD142 expression varies widely depending on the source and manufacturing process of the MSC product, additional clinical cell product characterization and guidelines are needed to ensure the safe use of MSC products. To minimize risk to patients receiving MSC therapy, we here propose to supplement the minimal criteria used for characterization of MSCs, to include criteria that assess the suitability of MSC products for intravascular use. If cell products are intended for intravascular delivery, which is true for half of all clinical applications involving MSCs, the effects of MSC on coagulation and hemocompatibility should be assessed and expression of TF/CD142 should be included as a phenotypic safety marker. This adjunct criterion will ensure both the identity of the MSCs as well as the safety of the MSCs has been vetted prior to intravascular delivery of MSC products.
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Affiliation(s)
- Guido Moll
- BIH Center for Regenerative Therapies (BCRT) and Berlin Brandenburg School of Regenerative Therapies (BSRT), Berlin Institute of Health (BIH) at the Charité—Universitätsmedizin Berlin, corporate member of Freie Universität zu Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Corresponding author: Guido Moll, PhD, BIH Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, D-13353 Berlin, Germany.
| | - James A Ankrum
- Roy J. Carver Department of Biomedical Engineering and Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA, USA
| | - Scott D Olson
- Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Sciences Center at Houston, Houston, TX, USA
| | - Jan A Nolta
- Director of the Stem Cell Program, University of California Davis School of Medicine, Sacramento, CA, USA
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Yiğenoğlu TN, Başcı S, Şahin D, Ulaş T, Dal MS, Korkmaz S, Hacıbekiroğlu T, Namdaroğlu S, Erkurt MA, Turgut B, Altuntaş F. Mesenchymal stem cell transfusion: Possible beneficial effects in COVID-19 patients. Transfus Apher Sci 2021; 60:103237. [PMID: 34419356 PMCID: PMC8372452 DOI: 10.1016/j.transci.2021.103237] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 07/15/2021] [Accepted: 08/08/2021] [Indexed: 02/06/2023]
Abstract
SARS-CoV-2 attaches to the angiotensin-converting enzyme 2 (ACE-2) receptor on human cells. The virus causes hypercytokinemia, capillary leak, pulmonary edema, acute respiratory distress syndrome, acute cardiac injury, and leads to death. Mesenchymal stem cells (MSCs) are ACE-2 negative cells; therefore, can escape from SARS-CoV-2. MSCs prevent hypercytokinemia and help the resolution of the pulmonary edema and other damages occurred during the course of COVID-19. In addition, MSCs enhance the regeneration of the lung and other tissues affected by SARS-CoV-2. The case series reported beneficial effect of MSCs in COVID-19 treatment. However, there are some concerns about the safety of MSCs, particularly referring to the increased risk of disseminated intravascular coagulation, and thromboembolism due to the expression of TF/CD142. Prospective, randomized, large scale studies are needed to reveal the optimum dose, administration way, time, efficacy, and safety of MSCs in the COVID-19 treatment.
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Affiliation(s)
- Tuğçe Nur Yiğenoğlu
- University of Health Sciences, Ankara Oncology Training and Research Hospital, Department of Hematology and Bone Marrow Transplantation Center, Ankara, Turkey
| | - Semih Başcı
- University of Health Sciences, Ankara Oncology Training and Research Hospital, Department of Hematology and Bone Marrow Transplantation Center, Ankara, Turkey,Corresponding author
| | - Derya Şahin
- University of Health Sciences, Ankara Oncology Training and Research Hospital, Department of Hematology and Bone Marrow Transplantation Center, Ankara, Turkey
| | - Turgay Ulaş
- Near East University, School of Medicine, Department of Internal Medicine, Department of Hematology, Cyprus
| | - Mehmet Sinan Dal
- University of Health Sciences, Ankara Oncology Training and Research Hospital, Department of Hematology and Bone Marrow Transplantation Center, Ankara, Turkey
| | - Serdal Korkmaz
- University of Health Sciences, Kayseri Training and Research Hospital, Department of Hematology and Bone Marrow Transplantation Center, Kayseri, Turkey
| | - Tuba Hacıbekiroğlu
- Sakarya University, School of Medicine, Department of Internal Medicine, Division of Hematology, Sakarya, Turkey
| | - Sinem Namdaroğlu
- University of Health Sciences, Bozyaka Training and Research Hospital, Department of Hematology and Bone Marrow Transplantation Center, Izmir, Turkey
| | - Mehmet Ali Erkurt
- Inonu University, School of Medicine, Department of Internal Medicine, Division of Hematology and Bone Marrow Transplantation Center, Malatya, Turkey
| | - Burhan Turgut
- Namık Kemal University, School of Medicine, Department of Internal Medicine, Division of Hematology and Bone Marrow Transplantation Center, Tekirdağ, Turkey
| | - Fevzi Altuntaş
- University of Health Sciences, Ankara Oncology Training and Research Hospital, Department of Hematology and Bone Marrow Transplantation Center, Ankara, Turkey,Ankara Yıldırım Beyazıt University, School of Medicine, Department of Internal Medicine, Division of Hematology, Ankara, Turkey
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Motavaf M, Piao X. Oligodendrocyte Development and Implication in Perinatal White Matter Injury. Front Cell Neurosci 2021; 15:764486. [PMID: 34803612 PMCID: PMC8599582 DOI: 10.3389/fncel.2021.764486] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 10/11/2021] [Indexed: 12/12/2022] Open
Abstract
Perinatal white matter injury (WMI) is the most common brain injury in premature infants and can lead to life-long neurological deficits such as cerebral palsy. Preterm birth is typically accompanied by inflammation and hypoxic-ischemic events. Such perinatal insults negatively impact maturation of oligodendrocytes (OLs) and cause myelination failure. At present, no treatment options are clinically available to prevent or cure WMI. Given that arrested OL maturation plays a central role in the etiology of perinatal WMI, an increased interest has emerged regarding the functional restoration of these cells as potential therapeutic strategy. Cell transplantation and promoting endogenous oligodendrocyte function are two potential options to address this major unmet need. In this review, we highlight the underlying pathophysiology of WMI with a specific focus on OL biology and their implication for the development of new therapeutic targets.
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Affiliation(s)
- Mahsa Motavaf
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Xianhua Piao
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, United States.,Newborn Brain Research Institute, University of California, San Francisco, San Francisco, CA, United States.,Weill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA, United States.,Division of Neonatology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, United States
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46
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Riedl J, Popp C, Eide C, Ebens C, Tolar J. Mesenchymal stromal cells in wound healing applications: role of the secretome, targeted delivery and impact on recessive dystrophic epidermolysis bullosa treatment. Cytotherapy 2021; 23:961-973. [PMID: 34376336 PMCID: PMC8569889 DOI: 10.1016/j.jcyt.2021.06.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/25/2021] [Accepted: 06/22/2021] [Indexed: 12/12/2022]
Abstract
Mesenchymal stromal cells (MSCs) are multi-potent stromal-derived cells capable of self-renewal that possess several advantageous properties for wound healing, making them of interest to the field of dermatology. Research has focused on characterizing the unique properties of MSCs, which broadly revolve around their regenerative and more recently discovered immunomodulatory capacities. Because of ease of harvesting and expansion, differentiation potential and low immunogenicity, MSCs have been leading candidates for tissue engineering and regenerative medicine applications for wound healing, yet results from clinical studies have been variable, and promising pre-clinical work has been difficult to reproduce. Therefore, the specific mechanisms of how MSCs influence the local microenvironment in distinct wound etiologies warrant further research. Of specific interest in MSC-mediated healing is harnessing the secretome, which is composed of components known to positively influence wound healing. Molecules released by the MSC secretome can promote re-epithelialization and angiogenesis while inhibiting fibrosis and microbial invasion. This review focuses on the therapeutic interest in MSCs with regard to wound healing applications, including burns and diabetic ulcers, with specific attention to the genetic skin disease recessive dystrophic epidermolysis bullosa. This review also compares various delivery methods to support skin regeneration in the hopes of combating the poor engraftment of MSCs after delivery, which is one of the major pitfalls in clinical studies utilizing MSCs.
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Affiliation(s)
- Julia Riedl
- Medical Scientist Training Program (MD/PhD), University of Minnesota, Minneapolis, Minnesota, USA; Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA
| | - Courtney Popp
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Cindy Eide
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Christen Ebens
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Jakub Tolar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA; Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA.
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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: 142] [Impact Index Per Article: 35.5] [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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48
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Ma D, Guan B, Song L, Liu Q, Fan Y, Zhao L, Wang T, Zhang Z, Gao Z, Li S, Xu H. A Bibliometric Analysis of Exosomes in Cardiovascular Diseases From 2001 to 2021. Front Cardiovasc Med 2021; 8:734514. [PMID: 34513962 PMCID: PMC8424118 DOI: 10.3389/fcvm.2021.734514] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/04/2021] [Indexed: 01/04/2023] Open
Abstract
Background: Exosomes in cardiovascular diseases (CVDs) have become an active research field with substantial value and potential. Nevertheless, there are few bibliometric studies in this field. We aimed to visualize the research hotspots and trends of exosomes in CVDs using a bibliometric analysis to help understand the future development of basic and clinical research. Methods: The articles and reviews regarding exosomes in the CVDs were culled from the Web of Science Core Collection, and knowledge maps were generated using CiteSpace and VOSviewer software. Results: A total of 1,039 articles were included. The number of exosome articles in the CVDs increased yearly. These publications came from 60 countries/regions, led by the US and China. The primary research institutions were Shanghai Jiao Tong University and Nanjing Medical University. Circulation Research was the journal and co-cited journal with the most studies. We identified 473 authors among which Lucio Barile had the most significant number of articles and Thery C was co-cited most often. After analysis, the most common keywords are myocardium infarction, microRNA and mesenchymal stem cells. Ischemic heart disease, pathogenesis, regeneration, stem cells, targeted therapy, biomarkers, cardiac protection, and others are current and developing areas of study. Conclusion: We identified the research hotspots and trends of exosomes in CVDs using bibliometric and visual methods. Research on exosomes is flourishing in the cardiovascular medicine. Regenerative medicine, exosome engineering, delivery vehicles, and biomarkers will likely become the focus of future research.
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Affiliation(s)
- Dan Ma
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Baoyi Guan
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Luxia Song
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Qiyu Liu
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Yixuan Fan
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Lin Zhao
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Tongxin Wang
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Zihao Zhang
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Zhuye Gao
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Siming Li
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Hao Xu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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49
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Xie Y, Chen F, Jia L, Chen R, Zhang VW, Zhong X, Wang D. Mesenchymal stem cells from different sources show distinct therapeutic effects in hyperoxia-induced bronchopulmonary dysplasia in rats. J Cell Mol Med 2021; 25:8558-8566. [PMID: 34322990 PMCID: PMC8419191 DOI: 10.1111/jcmm.16817] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/28/2021] [Accepted: 07/13/2021] [Indexed: 12/23/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have been shown as an effective medicinal means to treat bronchopulmonary dysplasia (BPD). The widely used MSCs were from Wharton's jelly of umbilical cord (UC-MSCs) and bone marrow (BM-MSCs). Amniotic fluid MSCs (AF-MSCs) may be produced before an individual is born to treat foetal diseases by autoplastic transplantation. We evaluated intratracheal (IT) MSCs as an approach to treat an hyperoxia-induced BPD animal model and compared the therapeutic effects between AF-, UC- and BM-MSCs. A BPD animal model was generated by exposing newborn rats to 95% O2 . The continued stress lasted 21 days, and the treatment of IT MSCs was conducted for 4 days. The therapeutic effects were analysed, including lung histology, level of inflammatory cytokines, cell death ratio and state of angiogenesis, by sacrificing the experimental animal at day 21. The lasting hyperoxia stress induced BPD similar to the biological phenotype. The treatment of IT MSCs was safe without deaths and normal organ histopathology. Specifically, the treatment was effective by inhibiting the alveolar dilatation, reducing inflammatory cytokines, inducing angiogenesis and lowering the cell death ratio. AF-MSCs had better therapeutic effects compared with UC-MSCs in relieving the pulmonary alveoli histological changes and promoting neovascularization, and UC-MSCs had the best immunosuppressive effect in plasma and lung lysis compared with AF-MSCs and BM-MSCs. This study demonstrated the therapeutic effects of AF-, UC- and BM-MSCs in BPD model. Superior treatment effect was provided by antenatal MSCs compared to BM-MSC in a statistical comparison.
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Affiliation(s)
- Yingjun Xie
- Department of Obstetrics and Gynecology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Fei Chen
- Department of Obstetrics and Gynecology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Lei Jia
- Reproductive Medicine Research Center, Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Rui Chen
- Department of Obstetrics and Gynecology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | | | - Xinqi Zhong
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Pediatrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ding Wang
- Department of Obstetrics and Gynecology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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50
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da Silva KN, Gobatto ALN, Costa-Ferro ZSM, Cavalcante BRR, Caria ACI, de Aragão França LS, Nonaka CKV, de Macêdo Lima F, Lopes-Pacheco M, Rocco PRM, de Freitas Souza BS. Is there a place for mesenchymal stromal cell-based therapies in the therapeutic armamentarium against COVID-19? Stem Cell Res Ther 2021; 12:425. [PMID: 34315546 PMCID: PMC8314259 DOI: 10.1186/s13287-021-02502-7] [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: 02/01/2021] [Accepted: 07/04/2021] [Indexed: 02/07/2023] Open
Abstract
The COVID-19 pandemic, caused by the rapid global spread of the novel coronavirus (SARS-CoV-2), has caused healthcare systems to collapse and led to hundreds of thousands of deaths. The clinical spectrum of COVID-19 is not only limited to local pneumonia but also represents multiple organ involvement, with potential for systemic complications. One year after the pandemic, pathophysiological knowledge has evolved, and many therapeutic advances have occurred, but mortality rates are still elevated in severe/critical COVID-19 cases. Mesenchymal stromal cells (MSCs) can exert immunomodulatory, antiviral, and pro-regenerative paracrine/endocrine actions and are therefore promising candidates for MSC-based therapies. In this review, we discuss the rationale for MSC-based therapies based on currently available preclinical and clinical evidence of safety, potential efficacy, and mechanisms of action. Finally, we present a critical analysis of the risks, limitations, challenges, and opportunities that place MSC-based products as a therapeutic strategy that may complement the current arsenal against COVID-19 and reduce the pandemic's unmet medical needs.
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Affiliation(s)
- Kátia Nunes da Silva
- Goncalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rua Waldemar Falcão, 121, Candeal, Salvador, Bahia, 40296-710, Brazil
- D'Or Institute for Research and Education (IDOR), Salvador, Brazil
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil
| | | | - Zaquer Suzana Munhoz Costa-Ferro
- D'Or Institute for Research and Education (IDOR), Salvador, Brazil
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil
| | - Bruno Raphael Ribeiro Cavalcante
- Goncalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rua Waldemar Falcão, 121, Candeal, Salvador, Bahia, 40296-710, Brazil
| | - Alex Cleber Improta Caria
- Graduate Program in Medicine and Health, Faculty of Medicine, Federal University of Bahia, Salvador, Brazil
| | - Luciana Souza de Aragão França
- D'Or Institute for Research and Education (IDOR), Salvador, Brazil
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil
| | - Carolina Kymie Vasques Nonaka
- D'Or Institute for Research and Education (IDOR), Salvador, Brazil
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil
| | | | - Miquéias Lopes-Pacheco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Patricia Rieken Macêdo Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Rio de Janeiro, Brazil
- COVID-19 Virus Network, Ministry of Science and Technology, and Innovation, Rio de Janeiro, Brazil
| | - Bruno Solano de Freitas Souza
- Goncalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rua Waldemar Falcão, 121, Candeal, Salvador, Bahia, 40296-710, Brazil.
- D'Or Institute for Research and Education (IDOR), Salvador, Brazil.
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador, Brazil.
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