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1
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Wlaschek M, Maity P, Koroma AK, Geiger H, Singh K, Scharffetter-Kochanek K. Imbalanced redox dynamics induce fibroblast senescence leading to impaired stem cell pools and skin aging. Free Radic Biol Med 2025; 233:292-301. [PMID: 40154755 DOI: 10.1016/j.freeradbiomed.2025.03.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 03/05/2025] [Accepted: 03/17/2025] [Indexed: 04/01/2025]
Abstract
Skin function depends on a meticulously regulated dynamic interaction of distinct skin compartments such as the epidermis and dermis. Adaptive responses at the molecular and cellular level are essential for these interactions - and if dysregulated - drive skin aging and other pathologies. After defining the role of redox homeodynamics in physiology and aging pathology, we focus on the redox distress-dependent aging of dermal fibroblasts including their progenitors. We here discuss the prime role of senescent fibroblasts in the control of their own endogenous niche and stem cell niches for epidermal stem cells, hair follicle stem cells, adipocyte precursors and muscle stem cells. We here review that redox imbalance induced reduction in Insulin-like Growth Factor-1 drives skin aging by the depletion of stem cell pools. This IGF-1 reduction is mediated via the redox-sensitive transcription factor JunB and also by the redox-dependent changes in sphingolipid-metabolism, among others. In addition, we will discuss the changes in the extracellular matrix of the skin affecting cellular senescence and the skin integrity and function in aging. The aim is a deeper understanding of the two main redox-dependent hubs such as JunB-induced depletion of IGF-1, and the sphingolipid-mediated remodeling of the cell membrane with its impact on IGF-1, fibroblast heterogeneity, function, senescence and plasticity in skin aging.
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Affiliation(s)
- Meinhard Wlaschek
- Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany; Aging Research Institute (arc), Ulm University, Ulm, Germany
| | - Pallab Maity
- Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany; Aging Research Institute (arc), Ulm University, Ulm, Germany
| | - Albert Kallon Koroma
- Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany; Aging Research Institute (arc), Ulm University, Ulm, Germany
| | - Hartmut Geiger
- Aging Research Institute (arc), Ulm University, Ulm, Germany; Institute for Molecular Medicine and Stem Cell Aging, Ulm University, Ulm, Germany
| | - Karmveer Singh
- Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany; Aging Research Institute (arc), Ulm University, Ulm, Germany
| | - Karin Scharffetter-Kochanek
- Department of Dermatology and Allergic Diseases, Ulm University, Ulm, Germany; Aging Research Institute (arc), Ulm University, Ulm, Germany.
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2
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Sadeghi M, Moghaddam A, Amiri AM, Charoghdoozi K, Mohammadi M, Dehnavi S, Orazizadeh M. Improving the Wound Healing Process: Pivotal role of Mesenchymal stromal/stem Cells and Immune Cells. Stem Cell Rev Rep 2025; 21:680-697. [PMID: 39921839 DOI: 10.1007/s12015-025-10849-0] [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] [Accepted: 01/31/2025] [Indexed: 02/10/2025]
Abstract
Wound healing, a physiological process, involves several different types of cells, from immune cells to non-immune cells, including mesenchymal stromal/stem cells (MSC), and their interactions. Immune cells including macrophages, neutrophils, dendritic cells (DC), innate lymphoid cells (ILC), natural killer (NK) cells, and B and T lymphocytes participate in wound healing by secreting various mediators and interacting with other cells. MSCs, as self-renewing, fast proliferating, and multipotent stromal/stem cells, are found in a wide variety of tissues and critically involved in different phases of wound healing by secreting various molecules that help to improve tissue healing and regeneration. In this review, first, we described the four main phases of wound healing, second, we reviewed the function of MSCs, MSC secretome and immune cells in improving the progress of wound repair (mainly focusing on skin wound healing), third, we explained the immune cells/MSCs interactions in the process of wound healing and regeneration, and finally, we introduce clinical applications of MSCs to improve the process of wound healing.
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Affiliation(s)
- Mahvash Sadeghi
- Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Asma Moghaddam
- Cellular and Molecular Research Center, Medical Basic Sciences Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Anatomical Sciences, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Amir Mohammad Amiri
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Kianush Charoghdoozi
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mojgan Mohammadi
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sajad Dehnavi
- Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mahmoud Orazizadeh
- Cellular and Molecular Research Center, Medical Basic Sciences Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Department of Anatomical Sciences, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Trigo CM, Rodrigues JS, Camões SP, Solá S, Miranda JP. Mesenchymal stem cell secretome for regenerative medicine: Where do we stand? J Adv Res 2025; 70:103-124. [PMID: 38729561 PMCID: PMC11976416 DOI: 10.1016/j.jare.2024.05.004] [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: 08/15/2023] [Revised: 02/27/2024] [Accepted: 05/03/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND Mesenchymal stem cell (MSC)-based therapies have yielded beneficial effects in a broad range of preclinical models and clinical trials for human diseases. In the context of MSC transplantation, it is widely recognized that the main mechanism for the regenerative potential of MSCs is not their differentiation, with in vivo data revealing transient and low engraftment rates. Instead, MSCs therapeutic effects are mainly attributed to its secretome, i.e., paracrine factors secreted by these cells, further offering a more attractive and innovative approach due to the effectiveness and safety of a cell-free product. AIM OF REVIEW In this review, we will discuss the potential benefits of MSC-derived secretome in regenerative medicine with particular focus on respiratory, hepatic, and neurological diseases. Both free and vesicular factors of MSC secretome will be detailed. We will also address novel potential strategies capable of improving their healing potential, namely by delivering important regenerative molecules according to specific diseases and tissue needs, as well as non-clinical and clinical studies that allow us to dissect their mechanisms of action. KEY SCIENTIFIC CONCEPTS OF REVIEW MSC-derived secretome includes both soluble and non-soluble factors, organized in extracellular vesicles (EVs). Importantly, besides depending on the cell origin, the characteristics and therapeutic potential of MSC secretome is deeply influenced by external stimuli, highlighting the possibility of optimizing their characteristics through preconditioning approaches. Nevertheless, the clarity around their mechanisms of action remains ambiguous, whereas the need for standardized procedures for the successful translation of those products to the clinics urges.
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Affiliation(s)
- Catarina M Trigo
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Joana S Rodrigues
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Sérgio P Camões
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Susana Solá
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Joana P Miranda
- Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
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4
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Mondal J, Zhang J, Qing F, Li S, Kumar D, Huse JT, Giancotti FG. Brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive niche. Nat Commun 2025; 16:1378. [PMID: 39910049 PMCID: PMC11799300 DOI: 10.1038/s41467-025-56347-2] [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: 04/26/2024] [Accepted: 01/16/2025] [Indexed: 02/07/2025] Open
Abstract
Metastasis in cancer is influenced by epigenetic factors. Using an in vivo screen, we demonstrate that several subunits of the polybromo-associated BAF (PBAF) chromatin remodeling complex, particularly Brd7, are required for maintaining breast cancer metastatic dormancy in the lungs of female mice. Brd7 loss induces metastatic reawakening, along with modifications in epigenomic landscapes and upregulated oncogenic signaling. Breast cancer cells harboring Brd7 inactivation also reprogram the surrounding immune microenvironment by downregulating MHC-1 expression and promoting a pro-metastatic cytokine profile. Flow cytometric and single-cell analyses reveal increased levels of pro-tumorigenic inflammatory and transitional neutrophils, CD8+ exhausted T cells, and CD4+ stress response T cells in lungs from female mice harboring Brd7-deficient metastases. Finally, attenuating this immunosuppressive milieu by neutrophil depletion, neutrophil extracellular trap (NET) inhibition, or immune checkpoint therapy abrogates metastatic outgrowth. These findings implicate Brd7 and PBAF in triggering metastatic outgrowth in cancer, pointing to targetable underlying mechanisms involving specific immune cell compartments.
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Affiliation(s)
- Jayanta Mondal
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Junfeng Zhang
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, China.
| | - Feng Qing
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, China
| | - Shunping Li
- Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong Province, China
| | - Dhiraj Kumar
- Cancer Metastasis Initiative, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York, USA
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA
- Johnson and Johnson Enterprise Innovations, Inc, Interventional Oncology, Spring House, PA, USA
| | - Jason T Huse
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Filippo G Giancotti
- Cancer Metastasis Initiative, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York, USA
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA
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5
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Hoseinzadeh A, Esmaeili SA, Sahebi R, Melak AM, Mahmoudi M, Hasannia M, Baharlou R. Fate and long-lasting therapeutic effects of mesenchymal stromal/stem-like cells: mechanistic insights. Stem Cell Res Ther 2025; 16:33. [PMID: 39901306 PMCID: PMC11792531 DOI: 10.1186/s13287-025-04158-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 01/21/2025] [Indexed: 02/05/2025] Open
Abstract
A large body of evidence suggests that mesenchymal stromal cells (MSCs) are able to respond rapidly to the cytokine milieu following systemic infusion. This encounter has the potential to dictate their therapeutic efficacy (also referred to as licensing). MSCs are able to rapidly react to cellular damage by migrating to the inflamed tissue and ultimately modifying the inflammatory microenvironment. However, the limited use of MSCs in clinical practice can be attributed to a lack of understanding of the fate of MSCs in patients after administration and long term MSC-derived therapeutic activity. While the known physiological effectors of viable MSCs make a relative contribution, an innate property of MSCs as a therapeutic agent is their caspase-dependent cell death. These mechanisms may be involving the functional reprogramming of myeloid phagocytes via efferocytosis, the process by which apoptotic bodies (ABs) are identified for engulfment by both specialized and non-specialized phagocytic cells. Recent studies have provided evidence that the uptake of ABs with a distinct genetic component can induce changes in gene expression through the process of epigenetic remodeling. This phenomenon, known as 'trained immunity', has a significant impact on immunometabolism processes. It is hypothesized that the diversity of recipient cells within the inflammatory stroma adjacent to MSCs may potentially serve as a biomarker for predicting the clinical outcome of MSC treatment, while also contributing to the variable outcomes observed with MSC-based therapies. Therefore, the long-term reconstructive process of MSCs may potentially be mediated by MSC apoptosis and subsequent phagocyte-mediated efferocytosis.
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Affiliation(s)
- Akram Hoseinzadeh
- Department of Immunology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Seyed-Alireza Esmaeili
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Sahebi
- Department of Modern Sciences and Technologies, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Mahmoud Mahmoudi
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maliheh Hasannia
- Cancer Research Center, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Rasoul Baharlou
- Department of Immunology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran.
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He Z, Starkuviene V, Keese M. The Differentiation and Regeneration Potential of ABCB5 + Mesenchymal Stem Cells: A Review and Clinical Perspectives. J Clin Med 2025; 14:660. [PMID: 39941329 PMCID: PMC11818130 DOI: 10.3390/jcm14030660] [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: 12/02/2024] [Revised: 01/15/2025] [Accepted: 01/19/2025] [Indexed: 02/16/2025] Open
Abstract
Mesenchymal stem cells (MSCs) are a family of multipotent stem cells that show self-renewal under proliferation, multilineage differentiation, immunomodulation, and trophic function. Thus, these cells, such as adipose tissue-derived mesenchymal stem cells (ADSCs), bone marrow-derived MSCs (BM-MSCs), and umbilical cord-derived mesenchymal stem cells (UC-MSCs), carry great promise for novel clinical treatment options. However, the challenges associated with the isolation of MSCs and the instability of their in vitro expansion remain significant barriers to their clinical application. The plasma membrane-spanning P-glycoprotein ATP-binding cassette subfamily B member 5 positive MSCs (ABCB5+ MSCs) derived from human skin specimens offer a distinctive advantage over other MSCs. They can be easily extracted from the dermis and expanded. In culture, ABCB5+ MSCs demonstrate robust innate homeostasis and a classic trilineage differentiation. Additionally, their ability to modulate the recipients' immune system highlights their potential for allogeneic applications in regenerative medicine. In this review, we primarily discuss the differentiation potential of ABCB5+ MSCs and their perspectives in regenerative medicine.
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Affiliation(s)
- Zheng He
- BioQuant, Heidelberg University, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany;
- European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Straße 13-17, 68167 Mannheim, Germany
| | - Vytaute Starkuviene
- BioQuant, Heidelberg University, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany;
- Institute of Biosciences, Vilnius University Life Sciences Center, 10257 Vilnius, Lithuania
| | - Michael Keese
- Department of Vascular Surgery, Theresienkrankenhaus, Bassermannstraße 1, 68165 Mannheim, Germany
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7
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Huang WC, Li YC, Chen PX, Ma KSK, Wang LT. Mesenchymal stem cell therapy as a game-changer in liver diseases: review of current clinical trials. Stem Cell Res Ther 2025; 16:3. [PMID: 39762946 PMCID: PMC11705688 DOI: 10.1186/s13287-024-04127-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 12/21/2024] [Indexed: 01/11/2025] Open
Abstract
Chronic liver diseases, including cirrhosis and liver failure, remain formidable challenges due to their complex progression and limited therapeutic options. Mesenchymal stem cell (MSC) therapy has emerged as a game-changing approach, leveraging its potent immunomodulatory, anti-fibrotic, and regenerative capabilities, along with the ability to transdifferentiate into hepatocytes. This review delves into the latest advances in MSC-based treatments for chronic and end-stage liver diseases, as highlighted in current clinical trials. MSCs derived from bone marrow and umbilical cord have shown remarkable promise in reversing liver damage, improving liver function, and providing hope for patients who do not respond to conventional therapies. When administered through hepatic, portal, or peripheral veins, MSCs have significantly improved liver histology, reduced fibrosis, and restored functional capacity. Furthermore, MSC-derived materials, such as extracellular vesicles and exosomes, are emerging as cutting-edge tools for treating liver failure and mitigating post-transplant complications. While autologous MSC-derived hepatocytes hold promise for non-fatal cirrhosis, allogeneic MSCs are being applied in more severe conditions, including liver failure and transplantation cases. Despite these promising early outcomes, larger trials and long-term studies are essential to fully harness MSCs as a transformative, off-the-shelf alternative to liver transplantation, heralding a new era in regenerative liver therapies.
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Affiliation(s)
- Wei-Chen Huang
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Laboratory of Clinical Immunology, National Defense Medical Center, Taipei, Taiwan
| | - Yuan-Chi Li
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 10F., Teaching & Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., Zhonghe Dist., Taipei, 235, Taiwan
| | - Pin-Xuan Chen
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 10F., Teaching & Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., Zhonghe Dist., Taipei, 235, Taiwan
| | - Kevin Sheng-Kai Ma
- Center for Global Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Li-Tzu Wang
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 10F., Teaching & Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., Zhonghe Dist., Taipei, 235, Taiwan.
- Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
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8
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Hazrati A, Mirarefin SMJ, Malekpour K, Rahimi A, Khosrojerdi A, Rasouli A, Akrami S, Soudi S. Mesenchymal stem cell application in pulmonary disease treatment with emphasis on their interaction with lung-resident immune cells. Front Immunol 2024; 15:1469696. [PMID: 39582867 PMCID: PMC11581898 DOI: 10.3389/fimmu.2024.1469696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/01/2024] [Indexed: 11/26/2024] Open
Abstract
Due to the vital importance of the lungs, lung-related diseases and their control are very important. Severe inflammatory responses mediated by immune cells were among the leading causes of lung tissue pathology and damage during the COVID-19 pandemic. In addition, uncontrolled immune cell responses can lead to lung tissue damage in other infectious and non-infectious diseases. It is essential to control immune responses in a way that leads to homeostasis. Immunosuppressive drugs only suppress inflammatory responses and do not affect the homeostasis of reactions. The therapeutic application of mesenchymal stem cells (MSCs), in addition to restoring immune homeostasis, can promote the regeneration of lung tissue through the production of growth factors and differentiation into lung-related cells. However, the communication between MSCs and immune cells after treatment of pulmonary diseases is essential, and investigating this can help develop a clinical perspective. Different studies in the clinical phase showed that MSCs can reverse fibrosis, increase regeneration, promote airway remodeling, and reduce damage to lung tissue. The proliferation and differentiation potential of MSCs is one of the mechanisms of their therapeutic effects. Furthermore, they can secrete exosomes that affect the function of lung cells and immune cells and change their function. Another important mechanism is that MSCs reduce harmful inflammatory responses through communication with innate and adaptive immune cells, which leads to a shift of the immune system toward regulatory and hemostatic responses.
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Affiliation(s)
- Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Arezou Rahimi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Arezou Khosrojerdi
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Ashkan Rasouli
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Susan Akrami
- Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Alsultan A, Farge D, Kili S, Forte M, Weiss DJ, Grignon F, Boelens JJ. International Society for Cell and Gene Therapy Clinical Translation Committee recommendations on mesenchymal stromal cells in graft-versus-host disease: easy manufacturing is faced with standardizing and commercialization challenges. Cytotherapy 2024; 26:1132-1140. [PMID: 38804990 PMCID: PMC12046531 DOI: 10.1016/j.jcyt.2024.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 05/03/2024] [Accepted: 05/03/2024] [Indexed: 05/29/2024]
Abstract
Mesenchymal stromal cells (MSCs) have been used in multiple clinical trials for steroid-refractory moderate-severe (grade II-IV) acute graft-versus-host disease (aGVHD) across the world over the last two decades. Despite very promising results in a variety of trials, it failed to get widespread approval by regulatory agencies such as the U.S. Food and Drug Administration and the European Medicines Agency. What lessons can we learn from this for future studies on MSCs and other cell therapy products? Broad heterogeneity among published trials using MSCs in aGVHD was likely the core problem. We propose a standardized approach in regards to donor-related factors, MSCs-related characteristics, as well as clinical trial design, to limit heterogeneity in trials for aGVHD and to fulfill the requirements of regulatory agencies. This approach may be expanded beyond MSCs to other Cell and Gene therapy products and trials in other diseases.
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Affiliation(s)
- Abdulrahman Alsultan
- Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Transplantation and Cellular Therapy, MSK Kids, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Dominique Farge
- Internal Medicine Unit (UF 04): CRMR MATHEC, Autoimmune diseases and Cellular Therapy, St-Louis Hospital, Center of reference for rare systemic autoimmune diseases of Ile-de-France (FAI2R), AP-HP, Hôpital St-Louis, Paris University, IRSL, Paris, France; Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Sven Kili
- Sven Kili Consulting Ltd., Shrewsbury, UK; Saisei Ventures, Boston, Massachusetts, USA; CCRM, Toronto, Canada
| | | | - Daniel J Weiss
- University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Felix Grignon
- International Society for Cell & Gene Therapy, Vancouver, Canada
| | - Jaap Jan Boelens
- Transplantation and Cellular Therapy, MSK Kids, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
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10
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Liu Y, Zhao C, Zhang R, Pang Y, Li L, Feng S. Progression of mesenchymal stem cell regulation on imbalanced microenvironment after spinal cord injury. Stem Cell Res Ther 2024; 15:343. [PMID: 39354635 PMCID: PMC11446099 DOI: 10.1186/s13287-024-03914-x] [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: 04/27/2024] [Accepted: 09/01/2024] [Indexed: 10/03/2024] Open
Abstract
Spinal cord injury (SCI) results in significant neural damage and inhibition of axonal regeneration due to an imbalanced microenvironment. Extensive evidence supports the efficacy of mesenchymal stem cell (MSC) transplantation as a therapeutic approach for SCI. This review aims to present an overview of MSC regulation on the imbalanced microenvironment following SCI, specifically focusing on inflammation, neurotrophy and axonal regeneration. The application, limitations and future prospects of MSC transplantation are discussed as well. Generally, a comprehensive perspective is provided for the clinical translation of MSC transplantation for SCI.
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Affiliation(s)
- Yifan Liu
- Department of Orthopaedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Lixia District, Jinan, 250012, Shandong, China
- Institute of Medical Sciences, The Second Hospital of Shandong University, Shandong University Center for Orthopaedics, Cheeloo College of Medicine, Shandong University, Jinan, 250033, Shandong, China
| | - Chenxi Zhao
- Department of Orthopaedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Lixia District, Jinan, 250012, Shandong, China
| | - Rong Zhang
- Department of Orthopaedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Lixia District, Jinan, 250012, Shandong, China
| | - Yilin Pang
- Department of Orthopaedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Lixia District, Jinan, 250012, Shandong, China
- Department of Orthopedics, International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
| | - Linquan Li
- Department of Orthopaedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Lixia District, Jinan, 250012, Shandong, China
| | - Shiqing Feng
- Department of Orthopaedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Lixia District, Jinan, 250012, Shandong, China.
- Institute of Medical Sciences, The Second Hospital of Shandong University, Shandong University Center for Orthopaedics, Cheeloo College of Medicine, Shandong University, Jinan, 250033, Shandong, China.
- Department of Orthopedics, International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.
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11
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Zorina A, Zorin V, Isaev A, Kudlay D, Manturova N, Ustugov A, Kopnin P. Current Status of Biomedical Products for Gene and Cell Therapy of Recessive Dystrophic Epidermolysis Bullosa. Int J Mol Sci 2024; 25:10270. [PMID: 39408598 PMCID: PMC11476579 DOI: 10.3390/ijms251910270] [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: 07/30/2024] [Revised: 08/22/2024] [Accepted: 08/27/2024] [Indexed: 10/20/2024] Open
Abstract
This detailed review describes innovative strategies and current products for gene and cell therapy at different stages of research and development to treat recessive dystrophic epidermolysis bullosa (RDEB) which is associated with the functional deficiency of collagen type VII alpha 1 (C7) caused by defects in the COL7A1 gene. The use of allogenic mesenchymal stem/stromal cells, which can be injected intradermally and intravenously, appears to be the most promising approach in the field of RDEB cell therapy. Injections of genetically modified autologous dermal fibroblasts are also worth mentioning under this framework. The most common methods of RDEB gene therapy are gene replacement using viral vectors and gene editing using programmable nucleases. Ex vivo epidermal transplants (ETs) based on autologous keratinocytes (Ks) have been developed using gene therapy methods; one such ET successively passed phase III clinical trials. Products based on the use of two-layer transplants have also been developed with both types of skin cells producing C7. Gene products have also been developed for local use. To date, significant progress has been achieved in the development of efficient biomedical products to treat RDEB, one of the most severe hereditary diseases.
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Affiliation(s)
- Alla Zorina
- Artgen Biotech, Moscow 119333, Russia; (A.Z.)
- Skincell LLC, Moscow 119333, Russia
| | - Vadim Zorin
- Artgen Biotech, Moscow 119333, Russia; (A.Z.)
- Skincell LLC, Moscow 119333, Russia
| | - Artur Isaev
- Artgen Biotech, Moscow 119333, Russia; (A.Z.)
| | - Dmitry Kudlay
- Department of Pharmacology, The I. M. Sechenov First Moscow State Medical University (The Sechenov University), Moscow 119991, Russia
- Department of Pharmacognosy and Industrial Pharmacy, Lomonosov Moscow State University, Moscow 119992, Russia
| | - Natalia Manturova
- Department of Plastic and Reconstructive surgery, Cosmetology and Cell Technologies, Pirogov Russian National Research Medical University, Moscow 117997, Russia
- JSC Plastic Surgery and Cosmetology Institute, Moscow 125047, Russia
| | - Andrei Ustugov
- Department of Plastic and Reconstructive surgery, Cosmetology and Cell Technologies, Pirogov Russian National Research Medical University, Moscow 117997, Russia
- JSC Plastic Surgery and Cosmetology Institute, Moscow 125047, Russia
| | - Pavel Kopnin
- Scientific Research Institute of Carcinogenesis, N. N. Blokhin National Medical Research Center of Oncology, Moscow 115522, Russia
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12
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Ju R, Gao X, Zhang C, Tang W, Tian W, He M. Exogenous MSC based tissue regeneration: a review of immuno-protection strategies from biomaterial scaffolds. J Mater Chem B 2024; 12:8868-8882. [PMID: 39171946 DOI: 10.1039/d4tb00778f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Abstract
Mesenchymal stem cell (MSC)-based tissue engineering holds great potential for regenerative medicine as a means of replacing damaged or lost tissues to restore their structure and function. However, the efficacy of MSC-based regeneration is frequently limited by the low survival rate and limited survival time of transplanted MSCs. Despite the inherent immune privileges of MSCs, such as low expression of major histocompatibility complex antigens, tolerogenic properties, local immunosuppressive microenvironment creation, and induction of immune tolerance, immune rejection remains a major obstacle to their survival and regenerative potential. Evidence suggests that immune protection strategies can enhance MSC therapeutic efficacy by prolonging their survival and maintaining their biological functions. Among various immune protection strategies, biomaterial-based scaffolds or cell encapsulation systems that mediate the interaction between transplanted MSCs and the host immune system or spatially isolate MSCs from the immune system for a specific time period have shown great promise. In this review, we provide a comprehensive overview of these biomaterial-based immune protection strategies employed for exogenous MSCs, highlighting the crucial role of modulating the immune microenvironment. Each strategy is critically examined, discussing its strengths, limitations, and potential applications in MSC-based tissue engineering. By elucidating the mechanisms behind immune rejection and exploring immune protection strategies, we aim to address the challenges faced by MSC-based tissue engineering and pave the way for enhancing the therapeutic outcomes of MSC therapies. The insights gained from this review will contribute to the development of more effective strategies to protect transplanted MSCs from immune rejection and enable their successful application in regenerative medicine.
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Affiliation(s)
- Rongbai Ju
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xinhui Gao
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Chi Zhang
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Wei Tang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Weidong Tian
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Min He
- Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
- National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
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Pharoun J, Berro J, Sobh J, Abou-Younes MM, Nasr L, Majed A, Khalil A, Joseph, Stephan, Faour WH. Mesenchymal stem cells biological and biotechnological advances: Implications for clinical applications. Eur J Pharmacol 2024; 977:176719. [PMID: 38849038 DOI: 10.1016/j.ejphar.2024.176719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 05/31/2024] [Accepted: 06/05/2024] [Indexed: 06/09/2024]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are multipotent stem cells that are able to differentiate into multiple lineages including bone, cartilage, muscle and fat. They hold immunomodulatory properties and therapeutic ability to treat multiple diseases, including autoimmune and chronic degenerative diseases. In this article, we reviewed the different biological properties, applications and clinical trials of MSCs. Also, we discussed the basics of manufacturing conditions, quality control, and challenges facing MSCs in the clinical setting. METHODS Extensive review of the literature was conducted through the databases PubMed, Google Scholar, and Cochrane. Papers published since 2015 and covering the clinical applications and research of MSC therapy were considered. Furthermore, older papers were considered when referring to pioneering studies in the field. RESULTS The most widely studied stem cells in cell therapy and tissue repair are bone marrow-derived mesenchymal stem cells. Adipose tissue-derived stem cells became more common and to a lesser extent other stem cell sources e.g., foreskin derived MSCs. MSCs therapy were also studied in the setting of COVID-19 infections, ischemic strokes, autoimmune diseases, tumor development and graft rejection. Multiple obstacles, still face the standardization and optimization of MSC therapy such as the survival and the immunophenotype and the efficiency of transplanted cells. MSCs used in clinical settings displayed heterogeneity in their function despite their extraction from healthy donors and expression of similar surface markers. CONCLUSION Mesenchymal stem cells offer a rising therapeutic promise in various diseases. However, their potential use in clinical applications requires further investigation.
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Affiliation(s)
- Jana Pharoun
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Jana Berro
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Jeanine Sobh
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | | | - Leah Nasr
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Ali Majed
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Alia Khalil
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Joseph
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Stephan
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Wissam H Faour
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36.
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14
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Herger N, Heggli I, Mengis T, Devan J, Arpesella L, Brunner F, Distler O, Dudli S. Impacts of priming on distinct immunosuppressive mechanisms of mesenchymal stromal cells under translationally relevant conditions. Stem Cell Res Ther 2024; 15:65. [PMID: 38443999 PMCID: PMC10916130 DOI: 10.1186/s13287-024-03677-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 02/21/2024] [Indexed: 03/07/2024] Open
Abstract
BACKGROUND The multimodal properties of mesenchymal stromal cells (MSCs), particularly their ability to modulate immune responses is of high interest in translational research. Pro-inflammatory, hypoxic, and 3D culture priming are promising and often used strategies to improve the immunosuppressive potency of MSCs, but the underlying mechanisms are not well understood. Therefore, the aims of this study were (i) to compare the effects of pro-inflammatory, hypoxic, and 3D culture priming on the in vitro immunosuppressive potential of MSCs, (ii) to assess if immunosuppressive priming effects are temporally preserved under standard and translationally relevant culture conditions, and (iii) to investigate if the three priming strategies engage the same immunosuppressive mechanisms. METHODS Functional in vitro T cell suppressive potency measurements were conducted to assess the impact of pro-inflammatory, hypoxic, and 3D culture priming on the immunosuppressive potential of human bone marrow-derived MSCs. Primed MSCs were either cultured under standard cell culture conditions or translationally relevant culture conditions, and their transcriptomic adaptations were monitored over time. Next-generation sequencing was performed to assess if different priming strategies activate distinct immunosuppressive mechanisms. RESULTS (i) Pro-inflammatory, hypoxic, and 3D culture priming induced profound transcriptomic changes in MSCs resulting in a significantly enhanced T cell suppressive potential of pro-inflammatory and 3D culture primed MSCs. (ii) Priming effects rapidly faded under standard cell culture conditions but were partially preserved under translationally relevant conditions. Interestingly, continuous 3D culture priming of MSCs maintained the immunosuppressive potency of MSCs. (iii) Next-generation sequencing revealed that priming strategy-specific differentially expressed genes are involved in the T cell suppressive capacity of MSCs, indicating that different priming strategies engage distinct immunosuppressive mechanisms. CONCLUSION Priming can be a useful approach to improve the immunosuppressive potency of MSCs. However, future studies involving primed MSCs should carefully consider the significant impact of translationally relevant conditions on the preservation of priming effects. Continuous 3D culture could act as a functionalized formulation, supporting the administration of MSC spheroids for a sustainably improved immunosuppressive potency.
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Affiliation(s)
- Nick Herger
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
- Department of Physical Medicine and Rheumatology, Balgrist University Hospital, University of Zurich, Balgrist Campus, Zurich, Switzerland.
| | - Irina Heggli
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Department of Physical Medicine and Rheumatology, Balgrist University Hospital, University of Zurich, Balgrist Campus, Zurich, Switzerland
| | - Tamara Mengis
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Department of Physical Medicine and Rheumatology, Balgrist University Hospital, University of Zurich, Balgrist Campus, Zurich, Switzerland
| | - Jan Devan
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Department of Physical Medicine and Rheumatology, Balgrist University Hospital, University of Zurich, Balgrist Campus, Zurich, Switzerland
| | - Leonardo Arpesella
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Department of Physical Medicine and Rheumatology, Balgrist University Hospital, University of Zurich, Balgrist Campus, Zurich, Switzerland
- Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC, Australia
| | - Florian Brunner
- Department of Physical Medicine and Rheumatology, Balgrist University Hospital, University of Zurich, Balgrist Campus, Zurich, Switzerland
| | - Oliver Distler
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Stefan Dudli
- Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Department of Physical Medicine and Rheumatology, Balgrist University Hospital, University of Zurich, Balgrist Campus, Zurich, Switzerland
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15
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Khaledi M, Zandi B, Mohsenipour Z. The Effect of Mesenchymal Stem Cells on the Wound Infection. Curr Stem Cell Res Ther 2024; 19:1084-1092. [PMID: 37815189 DOI: 10.2174/011574888x252482230926104342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 07/10/2023] [Accepted: 08/17/2023] [Indexed: 10/11/2023]
Abstract
Wound infection often requires a long period of care and an onerous treatment process. Also, the rich environment makes the wound an ideal niche for microbial growth. Stable structures, like biofilm, and drug-resistant strains cause a delay in the healing process, which has become one of the important challenges in wound treatment. Many studies have focused on alternative methods to deal the wound infections. One of the novel and highly potential ways is mesenchymal stromal cells (MSCs). MSCs are mesoderm-derived pluripotent adult stem cells with the capacity for self-renewal, multidirectional differentiation, and immunological control. Also, MSCs have anti-inflammatory and antiapoptotic effects. MScs, as pluripotent stromal cells, differentiate into many mature cells. Also, MSCs produce antimicrobial compounds, such as antimicrobial peptides (AMP), as well as secrete immune modulators, which are two basic features considered in wound healing. Despite the advantages, preserving the structure and activity of MSCs is considered one of the most important points in the treatment. MSCs' antimicrobial effects on microorganisms involved in wound infection have been confirmed in various studies. In this review, we aimed to discuss the antimicrobial and therapeutic applications of MSCs in the infected wound healing processes.
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Affiliation(s)
- Mansoor Khaledi
- Department of Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
- Department of Microbiology and Immunology, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Bita Zandi
- Department of Microbiology, Faculty of advanced science and technology, Tehran medical science, Islamic Azad University, Tehran, Iran
| | - Zeinab Mohsenipour
- Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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16
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Li Y, Wu Y, Huang J, Cao X, An Q, Peng Y, Zhao Y, Luo Y. A variety of death modes of neutrophils and their role in the etiology of autoimmune diseases. Immunol Rev 2024; 321:280-299. [PMID: 37850797 DOI: 10.1111/imr.13284] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2023]
Abstract
Neutrophils are important in the context of innate immunity and actively contribute to the progression of diverse autoimmune disorders. Distinct death mechanisms of neutrophils may exhibit specific and pivotal roles in autoimmune diseases and disease pathogenesis through the orchestration of immune homeostasis, the facilitation of autoantibody production, the induction of tissue and organ damage, and the incitement of pathological alterations. In recent years, more studies have provided in-depth examination of various neutrophil death modes, revealing nuances that challenge conventional understanding and underscoring their potential clinical utility in diagnosis and treatment. This review explores the multifaceted processes and characteristics of neutrophil death, with a focus on tailored investigations within various autoimmune diseases. It also highlights the potential interplay between neutrophil death and the landscape of autoimmune disorders. The review encapsulates the pertinent pathways implicated in various neutrophil death mechanisms across diverse autoimmune diseases while also charts possible avenues for future research.
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Affiliation(s)
- Yanhong Li
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yinlan Wu
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jingang Huang
- Medical Research Center, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xue Cao
- Department of Rheumatology and Immunology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou, Henan, China
| | - Qiyuan An
- School of Inspection and Biotechnology, Southern Medical University, Guangzhou, China
| | - Yun Peng
- Department of Rheumatology and Clinical Immunology, School of Medicine, The First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, China
| | - Yi Zhao
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yubin Luo
- Department of Rheumatology & Immunology, Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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17
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Burnham AJ, Foppiani EM, Goss KL, Jang-Milligan F, Kamalakar A, Bradley H, Goudy SL, Trochez CM, Dominici M, Daley-Bauer L, Gibson G, Horwitz EM. Differential response of mesenchymal stromal cells (MSCs) to type 1 ex vivo cytokine priming: implications for MSC therapy. Cytotherapy 2023; 25:1277-1284. [PMID: 37815775 DOI: 10.1016/j.jcyt.2023.08.014] [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: 06/01/2022] [Revised: 07/19/2023] [Accepted: 08/30/2023] [Indexed: 10/11/2023]
Abstract
BACKGROUND AIMS Mesenchymal stromal cells (MSCs) are polymorphic, adherent cells with the capability to stimulate tissue regeneration and modulate immunity. MSCs have been broadly investigated for potential therapeutic applications, particularly immunomodulatory properties, wound healing and tissue regeneration. The exact physiologic role of MSCs, however, remains poorly understood, and this gap in knowledge significantly impedes the rational development of therapeutic cells. Here, we considered interferon γ (IFN-γ) and tumor necrosis factor alpha (TNF-α), two cytokines likely encountered physiologically and commonly used in cell manufacturing. For comparison, we studied interleukin-10 (IL-10) (anti-inflammatory) and interleukin-4 (IL-4) (type 2 cytokine). METHODS We directly assessed the effects of these cytokines on bone marrow MSCs by comparing RNA Seq transcriptional profiles. Western blotting and flow cytometry were also used to evaluate effects of cytokine priming. RESULTS The type 1 cytokines (IFN-γ and TNF-α) induced striking changes in gene expression and remarkably different profiles from one another. Importantly, priming MSCs with either of these cytokines did not increase variability among multiple donors beyond what is intrinsic to non-primed MSCs from different donors. IFN-γ-primed MSCs expressed IDO1 and chemokines that recruit activated T cells. In contrast, TNF-α-primed MSCs expressed genes in alternate pathways, namely PGE2 and matrix metalloproteinases synthesis, and chemokines that recruit neutrophils. IL-10 and IL-4 priming had little to no effect. CONCLUSIONS Our data suggest that IFN-γ-primed MSCs may be a more efficacious immunosuppressive therapy aimed at diseases that target T cells (ie, graft-versus-host disease) compared with TNF-α-primed or non-primed MSCs, which may be better suited for therapies in other disease settings. These results contribute to our understanding of MSC bioactivity and suggest rational ex vivo cytokine priming approaches for MSC manufacturing and therapeutic applications.
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Affiliation(s)
- Andre J Burnham
- Department of Pediatrics, Marcus Center for Pediatric Cellular Therapy, Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Elisabetta M Foppiani
- Department of Pediatrics, Marcus Center for Pediatric Cellular Therapy, Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Kyndal L Goss
- Department of Pediatrics, Marcus Center for Pediatric Cellular Therapy, Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA; Division of Biologic and Biomedical Sciences, Laney Graduate School, Emory University Atlanta, Georgia, USA
| | - Fraser Jang-Milligan
- Department of Pediatrics, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
| | - Archana Kamalakar
- Department of Otolaryngology, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Heath Bradley
- Department of Otolaryngology, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Steven L Goudy
- Department of Otolaryngology, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA
| | | | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Lisa Daley-Bauer
- Department of Pediatrics, Marcus Center for Pediatric Cellular Therapy, Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Greg Gibson
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Edwin M Horwitz
- Department of Pediatrics, Marcus Center for Pediatric Cellular Therapy, Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA; Division of Biologic and Biomedical Sciences, Laney Graduate School, Emory University Atlanta, Georgia, USA.
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18
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Liu X, Zhou Z, Zeng WN, Zeng Q, Zhang X. The role of toll-like receptors in orchestrating osteogenic differentiation of mesenchymal stromal cells and osteoimmunology. Front Cell Dev Biol 2023; 11:1277686. [PMID: 37941898 PMCID: PMC10629627 DOI: 10.3389/fcell.2023.1277686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 10/11/2023] [Indexed: 11/10/2023] Open
Abstract
Osteoimmunology is a concept involving molecular and cellular crosstalk between the skeletal and immune systems. Toll-like receptors (TLRs) are widely expressed both on mesenchymal stromal cells (MSCs), the hematopoietic cells, and immune cells in the osteogenic microenvironment for bone development or repair. TLRs can sense both exogenous pathogen-associated molecular patterns (PAMPs) derived from microorganisms, and damage-associated molecular patterns (DAMPs) derived from normal cells subjected to injury, inflammation, or cell apoptosis under physiological or pathological conditions. Emerging studies reported that TLR signaling plays an important role in bone remodeling by directly impacting MSC osteogenic differentiation or osteoimmunology. However, how to regulate TLR signaling is critical and remains to be elucidated to promote the osteogenic differentiation of MSCs and new bone formation for bone tissue repair. This review outlines distinct TLR variants on MSCs from various tissues, detailing the impact of TLR pathway activation or inhibition on MSC osteogenic differentiation. It also elucidates TLR pathways' interplay with osteoclasts, immune cells, and extracellular vesicles (EVs) derived from MSCs. Furthermore, we explore biomaterial-based activation to guide MSCs' osteogenic differentiation. Therefore, understanding TLRs' role in this context has significant implications for advancing bone regeneration and repair strategies.
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Affiliation(s)
- Xiaoyang Liu
- Orthopedic Research Institution, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Zongke Zhou
- Orthopedic Research Institution, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Wei-Nan Zeng
- Orthopedic Research Institution, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Qin Zeng
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
- NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterials & Institute of Regulatory Science for Medical Devices & NMPA Research Base of Regulatory Science for Medical Devices, Sichuan University, Chengdu, China
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
- NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterials & Institute of Regulatory Science for Medical Devices & NMPA Research Base of Regulatory Science for Medical Devices, Sichuan University, Chengdu, China
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19
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Svistushkin M, Shpichka A, Bikmulina P, Fayzullin A, Zolotova A, Kosheleva N, Selezneva L, Shavkuta B, Lobacheva V, Nikiforova A, Kochetkov P, Kotova S, Starostina S, Shekhter A, Svistunov A, Svistushkin V, Timashev P. Vocal fold restoration after scarring: biocompatibility and efficacy of an MSC-based bioequivalent. Stem Cell Res Ther 2023; 14:303. [PMID: 37865795 PMCID: PMC10590531 DOI: 10.1186/s13287-023-03534-x] [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: 10/11/2023] [Indexed: 10/23/2023] Open
Abstract
BACKGROUND There is growing interest to application of regenerative medicine approaches in otorhinolaryngological practice, especially in the framework of the therapy of vocal fold (VF) scar lesions. The used conservative and surgical methods, despite the achieved positive outcomes, are frequently unpredictable and do not result in the restoration of the VF's lamina propria's structure, which provides the mechanical properties necessary for vibration. In this connection, the aim of this study was to ascertain the safety and efficacy of a bioequivalent in the treatment of VF scars using a rabbit model of chronic damage. METHODS The bioequivalent consisted of a hydrogel system based on a PEG-fibrin conjugate and human bone marrow-derived MSC. It was characterized and implanted heterotopically into rats and orthotopically into rabbits after VF scar excision. RESULTS We showed that the fabricated bioequivalent consisted of viable cells retaining their metabolic and proliferative activity. While being implanted heterotopically, it had induced the low inflammatory reaction in 7 days and was well tolerated. The orthotopic implantation showed that the gel application was characterized by a lower hemorrhage intensity (p = 0.03945). The intensity of stridor and respiratory rate between the groups in total and between separate groups had no statistically significant difference (p = 0.96 and p = 1; p = 0.9593 and p = 0.97…1, respectively). In 3 days post-implantation, MSC were detected only in the tissues closely surrounding the VF defect. The bioequivalent injection caused that the scar collagen fibers were packed looser and more frequently mutually parallel that is inherent in the native tissue (p = 0.018). In all experimental groups, the fibrous tissue's ingrowth in the adjacent exterior muscle tissue was observed; however, in Group 4 (PEG-Fibrin + MSC), it was much less pronounced than it was in Group 1 (normal saline) (p = 0.008). The difference between the thicknesses of the lamina propria in the control group and in Group 4 was not revealed to be statistically significant (p = 0.995). The Young's modulus of the VF after the bioequivalent implantation (1.15 ± 0.25 kPa) did not statistically significantly differ from the intact VF modulus (1.17 ± 0.45 kPa); therefore, the tissue properties in this group more closely resembled the intact VF. CONCLUSIONS The developed bioequivalent showed to be biocompatible and highly efficient in the restoration of VF's tissue.
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Affiliation(s)
| | - Anastasia Shpichka
- Institute for Regenerative Medicine, Sechenov University, Moscow, Russia
- Chemistry Department, Lomonosov Moscow State University, Moscow, Russia
| | - Polina Bikmulina
- Institute for Regenerative Medicine, Sechenov University, Moscow, Russia
| | - Alexey Fayzullin
- Institute for Regenerative Medicine, Sechenov University, Moscow, Russia
| | - Anna Zolotova
- Department for ENT Diseases, Sechenov University, Moscow, Russia
| | - Nastasia Kosheleva
- Institute for Regenerative Medicine, Sechenov University, Moscow, Russia
- FSBSI Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Liliya Selezneva
- Department for ENT Diseases, Sechenov University, Moscow, Russia
| | - Boris Shavkuta
- Institute for Regenerative Medicine, Sechenov University, Moscow, Russia
| | | | - Anna Nikiforova
- Department for ENT Diseases, Sechenov University, Moscow, Russia
| | - Peter Kochetkov
- Department for ENT Diseases, Sechenov University, Moscow, Russia
| | - Svetlana Kotova
- Institute for Regenerative Medicine, Sechenov University, Moscow, Russia
- Department of Polymers and Composites, N.N. Semenov Federal Research Center for Chemical Physics, Russian Academy of Sciences, Moscow, Russia
| | | | - Anatoly Shekhter
- Institute for Regenerative Medicine, Sechenov University, Moscow, Russia
| | | | | | - Peter Timashev
- Institute for Regenerative Medicine, Sechenov University, Moscow, Russia.
- Chemistry Department, Lomonosov Moscow State University, Moscow, Russia.
- World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov University, Moscow, Russia.
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20
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Al-Dhalimy AMB, Salim HM, Shather AH, Naser IH, Hizam MM, Alshujery MK. The pathological and therapeutically role of mesenchymal stem cell (MSC)-derived exosome in degenerative diseases; Particular focus on LncRNA and microRNA. Pathol Res Pract 2023; 250:154778. [PMID: 37683391 DOI: 10.1016/j.prp.2023.154778] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 08/17/2023] [Accepted: 08/20/2023] [Indexed: 09/10/2023]
Abstract
By releasing exosomes, which create the ideal milieu for the resolution of inflammation, mesenchymal stem cells (MSCs) enhance tissue healing and have strong immunomodulatory capabilities. MSCs-derived exosome also can affect tumor progress by a myriad of mechanisms. Exosomes function as a cell-cell communication tool to affect cellular activity in recipient cells and include an array of efficient bioactive chemicals. Understanding the fundamental biology of inflammation ablation, tissue homeostasis, and the creation of therapeutic strategies is particularly interested in the horizontal transfer of exosomal long non-coding RNAs (lncRNA) and microRNAs (miRNAs) to recipient cells, where they affect target gene expression. Herein, we propose an exosomal lncRNA and microRNA profile in neurological, renal, cardiac, lung, and liver diseases as well as skin wounds and arthritis.
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Affiliation(s)
| | - Haitham Mukhlif Salim
- Ministry of Health, Directorat of the Public Health, Health Promotion Departments, Baghdad, Iraq
| | - A H Shather
- Department of Computer Engineering Technology, Al Kitab University, Altun Kopru, Kirkuk 00964, Iraq
| | - Israa Habeeb Naser
- Medical Laboratories Techniques Department, AL-Mustaqbal University, 51001 Hillah, Babil, Iraq
| | - Manar Mohammed Hizam
- Collage of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
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21
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Xu W, Yang Y, Li N, Hua J. Interaction between Mesenchymal Stem Cells and Immune Cells during Bone Injury Repair. Int J Mol Sci 2023; 24:14484. [PMID: 37833933 PMCID: PMC10572976 DOI: 10.3390/ijms241914484] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 09/13/2023] [Accepted: 09/19/2023] [Indexed: 10/15/2023] Open
Abstract
Fractures are the most common large organ trauma in humans. The initial inflammatory response promotes bone healing during the initial post-fracture phase, but chronic and persistent inflammation due to infection or other factors does not contribute to the healing process. The precise mechanisms by which immune cells and their cytokines are regulated in bone healing remain unclear. The use of mesenchymal stem cells (MSCs) for cellular therapy of bone injuries is a novel clinical treatment approach. Bone progenitor MSCs not only differentiate into bone, but also interact with the immune system to promote the healing process. We review in vitro and in vivo studies on the role of the immune system and bone marrow MSCs in bone healing and their interactions. A deeper understanding of this paradigm may provide clues to potential therapeutic targets in the healing process, thereby improving the reliability and safety of clinical applications of MSCs to promote bone healing.
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Affiliation(s)
| | | | - Na Li
- Shaanxi Centre of Stem Cells Engineering & Technology, College of Veterinary Medicine, Northwest A&F University, Yangling, Xianyang 712100, China; (W.X.); (Y.Y.)
| | - Jinlian Hua
- Shaanxi Centre of Stem Cells Engineering & Technology, College of Veterinary Medicine, Northwest A&F University, Yangling, Xianyang 712100, China; (W.X.); (Y.Y.)
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22
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Li H, Yu S, Chen L, Liu H, Shen C. Immunomodulatory Role of Mesenchymal Stem Cells in Liver Transplantation: Status and Prospects. Dig Dis 2023; 42:41-52. [PMID: 37729883 DOI: 10.1159/000534003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 09/03/2023] [Indexed: 09/22/2023]
Abstract
BACKGROUND Liver transplantation (LT) is the only effective therapy for end-stage liver diseases, but some patients usually present with serious infection and immune rejection. Those with immune rejection require long-term administration of immunosuppressants, leading to serious adverse effects. Mesenchymal stem cells (MSCs) have various advantages in immune regulation and are promising drugs most likely to replace immunosuppressants. SUMMARY This study summarized the application of MSCs monotherapy, its combination with immunosuppressants, MSCs genetic modification, and MSCs derivative therapy (cell-free therapy) in LT. This may deepen the understanding of immunomodulatory role of MSCs and promote the application of MSCs in immune rejection treatment after LT. KEY MESSAGES MSCs could attenuate ischemia-reperfusion injury and immune rejection. There is no consensus on the effects of types and concentrations of immunosuppressants on MSCs. Although genetically modified MSCs have contributed to better outcomes to some extent, the best modification is still unclear. Besides, multiple clinical complications developed frequently after LT. Unfortunately, there are still few studies on the polygenic modification of MSCs for the simultaneous treatment of these complications. Therefore, more studies should be performed to investigate the potency of multi-gene modified MSCs in treating complications after LT. Additionally, MSC derivatives mainly include exosomes, extracellular vesicles, and conditioned medium. Despite therapeutic effects, these three therapies still have some limitations such as heterogeneity between generations and that they cannot be quantified accurately.
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Affiliation(s)
- Haitao Li
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Saihua Yu
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
| | - Lihong Chen
- Department of Pathology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Hongzhi Liu
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Conglong Shen
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
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23
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Sionov RV, Ahdut-HaCohen R. A Supportive Role of Mesenchymal Stem Cells on Insulin-Producing Langerhans Islets with a Specific Emphasis on The Secretome. Biomedicines 2023; 11:2558. [PMID: 37761001 PMCID: PMC10527322 DOI: 10.3390/biomedicines11092558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/06/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Type 1 Diabetes (T1D) is a chronic autoimmune disease characterized by a gradual destruction of insulin-producing β-cells in the endocrine pancreas due to innate and specific immune responses, leading to impaired glucose homeostasis. T1D patients usually require regular insulin injections after meals to maintain normal serum glucose levels. In severe cases, pancreas or Langerhans islet transplantation can assist in reaching a sufficient β-mass to normalize glucose homeostasis. The latter procedure is limited because of low donor availability, high islet loss, and immune rejection. There is still a need to develop new technologies to improve islet survival and implantation and to keep the islets functional. Mesenchymal stem cells (MSCs) are multipotent non-hematopoietic progenitor cells with high plasticity that can support human pancreatic islet function both in vitro and in vivo and islet co-transplantation with MSCs is more effective than islet transplantation alone in attenuating diabetes progression. The beneficial effect of MSCs on islet function is due to a combined effect on angiogenesis, suppression of immune responses, and secretion of growth factors essential for islet survival and function. In this review, various aspects of MSCs related to islet function and diabetes are described.
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Affiliation(s)
- Ronit Vogt Sionov
- The Institute of Biomedical and Oral Research (IBOR), Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Ronit Ahdut-HaCohen
- Department of Medical Neurobiology, Institute of Medical Research, Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel;
- Department of Science, The David Yellin Academic College of Education, Jerusalem 9103501, Israel
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24
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Quarato ER, Salama NA, Li AJ, Smith CO, Zhang J, Kawano Y, McArthur M, Liesveld JL, Becker MW, Elliott MR, Eliseev RA, Calvi LM. Efferocytosis by bone marrow mesenchymal stromal cells disrupts osteoblastic differentiation via mitochondrial remodeling. Cell Death Dis 2023; 14:428. [PMID: 37452070 PMCID: PMC10349065 DOI: 10.1038/s41419-023-05931-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 06/12/2023] [Accepted: 06/26/2023] [Indexed: 07/18/2023]
Abstract
The efficient clearance of dead and dying cells, efferocytosis, is critical to maintain tissue homeostasis. In the bone marrow microenvironment (BMME), this role is primarily fulfilled by professional bone marrow macrophages, but recent work has shown that mesenchymal stromal cells (MSCs) act as a non-professional phagocyte within the BMME. However, little is known about the mechanism and impact of efferocytosis on MSCs and on their function. To investigate, we performed flow cytometric analysis of neutrophil uptake by ST2 cells, a murine bone marrow-derived stromal cell line, and in murine primary bone marrow-derived stromal cells. Transcriptional analysis showed that MSCs possess the necessary receptors and internal processing machinery to conduct efferocytosis, with Axl and Tyro3 serving as the main receptors, while MerTK was not expressed. Moreover, the expression of these receptors was modulated by efferocytic behavior, regardless of apoptotic target. MSCs derived from human bone marrow also demonstrated efferocytic behavior, showing that MSC efferocytosis is conserved. In all MSCs, efferocytosis impaired osteoblastic differentiation. Transcriptional analysis and functional assays identified downregulation in MSC mitochondrial function upon efferocytosis. Experimentally, efferocytosis induced mitochondrial fission in MSCs. Pharmacologic inhibition of mitochondrial fission in MSCs not only decreased efferocytic activity but also rescued osteoblastic differentiation, demonstrating that efferocytosis-mediated mitochondrial remodeling plays a critical role in regulating MSC differentiation. This work describes a novel function of MSCs as non-professional phagocytes within the BMME and demonstrates that efferocytosis by MSCs plays a key role in directing mitochondrial remodeling and MSC differentiation. Efferocytosis by MSCs may therefore be a novel mechanism of dysfunction and senescence. Since our data in human MSCs show that MSC efferocytosis is conserved, the consequences of MSC efferocytosis may impact the behavior of these cells in the human skeleton, including bone marrow remodeling and bone loss in the setting of aging, cancer and other diseases.
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Affiliation(s)
- Emily R Quarato
- Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, USA.
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
| | - Noah A Salama
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA
| | - Allison J Li
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Charles O Smith
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
| | - Jane Zhang
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Yuko Kawano
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Matthew McArthur
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
| | - Jane L Liesveld
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Michael W Becker
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Michael R Elliott
- University of Virginia, Department of Microbiology, Immunology, and Cancer Biology, Charlottesville, VA, USA
| | - Roman A Eliseev
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA
- Department of Orthopedics, University of Rochester Medical Center, Rochester, NY, USA
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Laura M Calvi
- James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
- Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, USA.
- Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA.
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25
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Yang G, Fan X, Liu Y, Jie P, Mazhar M, Liu Y, Dechsupa N, Wang L. Immunomodulatory Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells. Stem Cell Rev Rep 2023; 19:1214-1231. [PMID: 37058201 PMCID: PMC10103048 DOI: 10.1007/s12015-023-10539-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/29/2023] [Indexed: 04/15/2023]
Abstract
Mesenchymal stem cells (MSCs) are regarded as highly promising cells for allogeneic cell therapy, owing to their multipotent nature and ability to display potent and varied functions in different diseases. The functions of MSCs, including native immunomodulation, high self-renewal characteristic, and secretory and trophic properties, can be employed to improve the immune-modulatory functions in diseases. MSCs impact most immune cells by directly contacting and/or secreting positive microenvironmental factors to influence them. Previous studies have reported that the immunomodulatory role of MSCs is basically dependent on their secretion ability from MSCs. This review discusses the immunomodulatory capabilities of MSCs and the promising strategies to successfully improve the potential utilization of MSCs in clinical research.
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Affiliation(s)
- Guoqiang Yang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- Acupuncture and Rehabilitation Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Xuehui Fan
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention of Cardiovascular Diseases, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany
| | - Yingchun Liu
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Pingping Jie
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Maryam Mazhar
- National Traditional Chinese Medicine Clinical Research Base and Drug Research Center of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Yong Liu
- Department of Magnetic Resonance Imaging, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China.
| | - Nathupakorn Dechsupa
- Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.
| | - Li Wang
- Research Center for Integrated Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China.
- Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, China.
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26
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Dieter K, Niebergall-Roth E, Daniele C, Fluhr S, Frank NY, Ganss C, Kiritsi D, McGrath JA, Tolar J, Frank MH, Kluth MA. ABCB5 + mesenchymal stromal cells facilitate complete and durable wound closure in recessive dystrophic epidermolysis bullosa. Cytotherapy 2023; 25:782-788. [PMID: 36868990 PMCID: PMC10257763 DOI: 10.1016/j.jcyt.2023.01.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/30/2023] [Accepted: 01/31/2023] [Indexed: 03/05/2023]
Abstract
BACKGROUND AND AIMS Recessive dystrophic epidermolysis bullosa (RDEB) is a hereditary, rare, devastating and life-threatening skin fragility disorder with a high unmet medical need. In a recent international, single-arm clinical trial, treatment of 16 patients (aged 6-36 years) with three intravenous infusions of 2 × 106 immunomodulatory ABCB5+ dermal mesenchymal stromal cells (MSCs)/kg on days 0, 17 and 35 reduced disease activity, itch and pain. A post-hoc analysis was undertaken to assess the potential effects of treatment with ABCB5+ MSCs on the overall skin wound healing in patients suffering from RDEB. METHODS Documentary photographs of the affected body regions taken on days 0, 17, 35 and at 12 weeks were evaluated regarding proportion, temporal course and durability of wound closure as well as development of new wounds. RESULTS Of 168 baseline wounds in 14 patients, 109 (64.9%) wounds had closed at week 12, of which 63.3% (69 wounds) had closed already by day 35 or day 17. Conversely, 74.2% of the baseline wounds that had closed by day 17 or day 35 remained closed until week 12. First-closure ratio within 12 weeks was 75.6%. The median rate of newly developing wounds decreased significantly (P = 0.001) by 79.3%. CONCLUSIONS Comparison of the findings with published data from placebo arms and vehicle-treated wounds in controlled clinical trials suggests potential capability of ABCB5+ MSCs to facilitate wound closure, prolongate wound recurrence and decelerate formation of new wounds in RDEB. Beyond suggesting therapeutic efficacy for ABCB5+ MSCs, the analysis might stimulate researchers who develop therapies for RDEB and other skin fragility disorders to not only assess closure of preselected target wounds but pay attention to the patients' dynamic and diverse overall wound presentation as well as to the durability of achieved wound closure and the development of new wounds. TRIAL REGISTRATION Clinicaltrials.gov NCT03529877; EudraCT 2018-001009-98.
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Affiliation(s)
| | | | | | | | - Natasha Y Frank
- Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Transplant Research Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
| | - Christoph Ganss
- RHEACELL GmbH & Co. KG, Heidelberg, Germany; TICEBA GmbH, Heidelberg, Germany
| | - Dimitra Kiritsi
- Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - John A McGrath
- St John's Institute of Dermatology, Guy's Hospital, King's College London, London, UK
| | - Jakub Tolar
- Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Pediatrics, University of Minnesota M Health Fairview Masonic Children's Hospital, Minneapolis, Minnesota, USA
| | - Markus H Frank
- Transplant Research Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA; Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; School of Medical and Health Sciences, Edith Cowan University, Perth, Western Australia, Australia
| | - Mark A Kluth
- RHEACELL GmbH & Co. KG, Heidelberg, Germany; TICEBA GmbH, Heidelberg, Germany.
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27
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Niebergall-Roth E, Dieter K, Daniele C, Fluhr S, Khokhrina M, Silva I, Ganss C, Frank MH, Kluth MA. Kinetics of Wound Development and Healing Suggests a Skin-Stabilizing Effect of Allogeneic ABCB5 + Mesenchymal Stromal Cell Treatment in Recessive Dystrophic Epidermolysis Bullosa. Cells 2023; 12:1468. [PMID: 37296590 PMCID: PMC10252830 DOI: 10.3390/cells12111468] [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: 05/02/2023] [Revised: 05/19/2023] [Accepted: 05/23/2023] [Indexed: 06/12/2023] Open
Abstract
Recessive dystrophic epidermolysis (RDEB) is a rare, inherited, and currently incurable skin blistering disorder characterized by cyclically recurring wounds coexisting with chronic non-healing wounds. In a recent clinical trial, three intravenous infusions of skin-derived ABCB5+ mesenchymal stromal cells (MSCs) to 14 patients with RDEB improved the healing of wounds that were present at baseline. Since in RDEB even minor mechanical forces perpetually provoke the development of new or recurrent wounds, a post-hoc analysis of patient photographs was performed to specifically assess the effects of ABCB5+ MSCs on new or recurrent wounds by evaluating 174 wounds that occurred after baseline. During 12 weeks of systemic treatment with ABCB5+ MSCs, the number of newly occurring wounds declined. When compared to the previously reported healing responses of the wounds present at baseline, the newly occurring wounds healed faster, and a greater portion of healed wounds remained stably closed. These data suggest a previously undescribed skin-stabilizing effect of treatment with ABCB5+ MSCs and support repeated dosing of ABCB5+ MSCs in RDEB to continuously slow the wound development and accelerate the healing of new or recurrent wounds before they become infected or progress to a chronic, difficult-to-heal stage.
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Affiliation(s)
| | | | | | - Silvia Fluhr
- RHEACELL GmbH & Co. KG, 69120 Heidelberg, Germany
| | | | - Ines Silva
- RHEACELL GmbH & Co. KG, 69120 Heidelberg, Germany
| | | | - Markus H. Frank
- Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
- Transplant Research Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- School of Medical and Health Sciences, Edith Cowan University, Perth 6027, Australia
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28
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Han L, Wu X, Wang O, Luan X, Velander WH, Aynardi M, Halstead ES, Bonavia AS, Jin R, Li G, Li Y, Wang Y, Dong C, Lei Y. Mesenchymal stromal cells and alpha-1 antitrypsin have a strong synergy in modulating inflammation and its resolution. Theranostics 2023; 13:2843-2862. [PMID: 37284443 PMCID: PMC10240832 DOI: 10.7150/thno.83942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 04/25/2023] [Indexed: 06/08/2023] Open
Abstract
Rationale: Trauma, surgery, and infection can cause severe inflammation. Both dysregulated inflammation intensity and duration can lead to significant tissue injuries, organ dysfunction, mortality, and morbidity. Anti-inflammatory drugs such as steroids and immunosuppressants can dampen inflammation intensity, but they derail inflammation resolution, compromise normal immunity, and have significant adverse effects. The natural inflammation regulator mesenchymal stromal cells (MSCs) have high therapeutic potential because of their unique capabilities to mitigate inflammation intensity, enhance normal immunity, and accelerate inflammation resolution and tissue healing. Furthermore, clinical studies have shown that MSCs are safe and effective. However, they are not potent enough, alone, to completely resolve severe inflammation and injuries. One approach to boost the potency of MSCs is to combine them with synergistic agents. We hypothesized that alpha-1 antitrypsin (A1AT), a plasma protein used clinically and has an excellent safety profile, was a promising candidate for synergism. Methods: This investigation examined the efficacy and synergy of MSCs and A1AT to mitigate inflammation and promote resolution, using in vitro inflammatory assay and in vivo mouse acute lung injury model. The in vitro assay measured cytokine releases, inflammatory pathways, reactive oxygen species (ROS), and neutrophil extracellular traps (NETs) production by neutrophils and phagocytosis in different immune cell lines. The in vivo model monitored inflammation resolution, tissue healing, and animal survival. Results: We found that the combination of MSCs and A1AT was much more effective than each component alone in i) modulating cytokine releases and inflammatory pathways, ii) inhibiting ROS and NETs production by neutrophils, iii) enhancing phagocytosis and, iv) promoting inflammation resolution, tissue healing, and animal survival. Conclusion: These results support the combined use of MSCs, and A1AT is a promising approach for managing severe, acute inflammation.
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Affiliation(s)
- Li Han
- Department of Biomedical Engineering, Pennsylvania State University; University Park, PA, 16802, USA
- Huck Institutes of the Life Sciences, Pennsylvania State University; University Park, PA, 16802, USA
| | - Xinran Wu
- Department of Biomedical Engineering, Pennsylvania State University; University Park, PA, 16802, USA
| | - Ou Wang
- Department of Chemical and Biomolecular Engineering, University of Nebraska-Lincoln; Lincoln, NE, 68588, USA
| | - Xiao Luan
- Biomedical Center of Qingdao University; Qingdao, Shandong, 266000, China
| | - William H. Velander
- Department of Chemical and Biomolecular Engineering, University of Nebraska-Lincoln; Lincoln, NE, 68588, USA
| | - Michael Aynardi
- Department of Orthopedics Surgery, Pennsylvania State University College of Medicine; Hershey, PA, 17033, USA
| | - E. Scott Halstead
- Division of Pediatric Critical Care Medicine, Department of Pediatrics, Pennsylvania State Milton S Hershey Medical Center; Hershey, PA, 17033, USA
| | - Anthony S. Bonavia
- Division of Critical Care Medicine, Department of Anesthesiology and Perioperative Medicine, Pennsylvania State Milton S Hershey Medical Center; Hershey, PA, 17033, USA
| | - Rong Jin
- Department of Neurosurgery, Pennsylvania State Milton S Hershey Medical Center; Hershey, PA, 17033, USA
| | - Guohong Li
- Department of Neurosurgery, Pennsylvania State Milton S Hershey Medical Center; Hershey, PA, 17033, USA
| | - Yulong Li
- Department of Emergency Medicine, University of Nebraska Medical Center; Omaha, NE, 68105, USA
| | - Yong Wang
- Department of Biomedical Engineering, Pennsylvania State University; University Park, PA, 16802, USA
| | - Cheng Dong
- Department of Biomedical Engineering, Pennsylvania State University; University Park, PA, 16802, USA
| | - Yuguo Lei
- Department of Biomedical Engineering, Pennsylvania State University; University Park, PA, 16802, USA
- Huck Institutes of the Life Sciences, Pennsylvania State University; University Park, PA, 16802, USA
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29
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Tamasi V, Németh K, Csala M. Role of Extracellular Vesicles in Liver Diseases. Life (Basel) 2023; 13:life13051117. [PMID: 37240762 DOI: 10.3390/life13051117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 04/24/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023] Open
Abstract
Extracellular vesicles (EVs) are cell-derived membrane structures that are formed by budding from the plasma membrane or originate from the endosomal system. These microparticles (100 nm-100 µm) or nanoparticles (>100 nm) can transport complex cargos to other cells and, thus, provide communication and intercellular regulation. Various cells, such as hepatocytes, liver sinusoidal endothelial cells (LSECs) or hepatic stellate cells (HSCs), secrete and take up EVs in the healthy liver, and the amount, size and content of these vesicles are markedly altered under pathophysiological conditions. A comprehensive knowledge of the modified EV-related processes is very important, as they are of great value as biomarkers or therapeutic targets. In this review, we summarize the latest knowledge on hepatic EVs and the role they play in the homeostatic processes in the healthy liver. In addition, we discuss the characteristic changes of EVs and their potential exacerbating or ameliorating effects in certain liver diseases, such as non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), drug induced liver injury (DILI), autoimmune hepatitis (AIH), hepatocarcinoma (HCC) and viral hepatitis.
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Affiliation(s)
- Viola Tamasi
- Department of Molecular Biology, Semmelweis University, 1094 Budapest, Hungary
| | - Krisztina Németh
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, 1089 Budapest, Hungary
- ELKH-SE Translational Extracellular Vesicle Research Group, 1085 Budapest, Hungary
| | - Miklós Csala
- Department of Molecular Biology, Semmelweis University, 1094 Budapest, Hungary
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Cho WJ, Mittal SK, Chauhan SK. Mesenchymal Stromal Cells Suppress T-Cell-Mediated Delayed-Type Hypersensitivity via ALCAM-CD6 Interaction. Stem Cells Transl Med 2023; 12:221-233. [PMID: 36972356 PMCID: PMC10108723 DOI: 10.1093/stcltm/szad012] [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: 11/09/2022] [Accepted: 02/06/2023] [Indexed: 03/29/2023] Open
Abstract
Mounting evidence suggests mesenchymal stromal cells (MSCs) suppress CD4+ T-cell activation, but whether MSCs directly regulate activation and expansion of allogeneic T cells has not been fully deciphered. Here, we identified that both human and murine MSCs constitutively express ALCAM, a cognate ligand for CD6 receptors on T cells, and investigated its immunomodulatory function using in vivo and in vitro experiments. Our controlled coculture assays demonstrated that ALCAM-CD6 pathway is critical for MSCs to exert its suppressive function on early CD4+CD25- T-cell activation. Moreover, neutralizing ALCAM or CD6 results in the abrogation of MSC-mediated suppression of T-cell expansion. Using a murine model of delayed-type hypersensitivity response to alloantigen, we show that ALCAM-silenced MSCs lose the capacity to suppress the generation of alloreactive IFNγ-secreting T cells. Consequently, MSCs, following ALCAM knockdown, failed to prevent allosensitization and alloreactive T-cell-mediated tissue damage.
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Affiliation(s)
- WonKyung J Cho
- Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Sharad K Mittal
- Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Sunil K Chauhan
- Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA, USA
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31
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Yan K, Zheng J, Kluth MA, Li L, Ganss C, Yard B, Magdeburg R, Frank MH, Pallavi P, Keese M. ABCB5 + mesenchymal stromal cells therapy protects from hypoxia by restoring Ca 2+ homeostasis in vitro and in vivo. Stem Cell Res Ther 2023; 14:24. [PMID: 36759868 PMCID: PMC9912525 DOI: 10.1186/s13287-022-03228-w] [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: 03/14/2022] [Accepted: 12/21/2022] [Indexed: 02/11/2023] Open
Abstract
BACKGROUND Hypoxia in ischemic disease impairs Ca2+ homeostasis and may promote angiogenesis. The therapeutic efficacy of mesenchymal stromal cells (MSCs) in peripheral arterial occlusive disease is well established, yet its influence on cellular Ca2+ homeostasis remains to be elucidated. We addressed the influence of ATP-binding cassette subfamily B member 5 positive mesenchymal stromal cells (ABCB5+ MSCs) on Ca2+ homeostasis in hypoxic human umbilical vein endothelial cells (HUVECs) in vitro and in vivo. METHODS Hypoxia was induced in HUVECs by Cobalt (II) chloride (CoCl2) or Deferoxamine (DFO). Dynamic changes in the cytosolic- and endoplasmic reticulum (ER) Ca2+ and changes in reactive oxygen species were assessed by appropriate fluorescence-based sensors. Metabolic activity, cell migration, and tube formation were assessed by standard assays. Acute-on-chronic ischemia in Apolipoprotein E knock-out (ApoE-/-) mice was performed by double ligation of the right femoral artery (DFLA). ABCB5+ MSC cells were injected into the ischemic limb. Functional recovery after DFLA and histology of gastrocnemius and aorta were assessed. RESULTS Hypoxia-induced impairment of cytosolic and ER Ca2+ were restored by ABCB5+ MSCs or their conditioned medium. Similar was found for changes in intracellular ROS production, metabolic activity, migratory ability and tube formation. The restoration was paralleled by an increased expression of the Ca2+ transporter Sarco-/endoplasmic reticulum ATPase 2a (SERCA2a) and the phosphorylation of Phospholamban (PLN). In acute-on-chronic ischemia, ABCB5+ MSCs treated mice showed a higher microvascular density, increased SERCA2a expression and PLN phosphorylation relative to untreated controls. CONCLUSIONS ABCB5+ MSCs therapy can restore cellular Ca2+ homeostasis, which may beneficially affect the angiogenic function of endothelial cells under hypoxia in vitro and in vivo.
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Affiliation(s)
- Kaixuan Yan
- grid.7700.00000 0001 2190 4373Department of Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany ,grid.7700.00000 0001 2190 4373European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Jiaxing Zheng
- grid.7700.00000 0001 2190 4373Department of Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany ,grid.7700.00000 0001 2190 4373European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | | | - Lin Li
- grid.7700.00000 0001 2190 4373Department of Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany ,grid.7700.00000 0001 2190 4373European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Christoph Ganss
- TICEBA GmbH, Heidelberg, Germany ,grid.476673.7RHEACELL GmbH & Co. KG, Heidelberg, Germany
| | - Benito Yard
- grid.7700.00000 0001 2190 4373V Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Richard Magdeburg
- grid.411778.c0000 0001 2162 1728Department of Surgery, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68161 Mannheim, Germany
| | - Markus H. Frank
- grid.38142.3c000000041936754XDepartment of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA ,grid.38142.3c000000041936754XTransplant Research Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA USA ,grid.38142.3c000000041936754XHarvard Stem Cell Institute, Harvard University, Cambridge, MA USA ,grid.1038.a0000 0004 0389 4302School of Medical and Health Sciences, Edith Cowan University, Perth, WA Australia
| | - Prama Pallavi
- Department of Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. .,European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. .,Department of Surgery, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68161, Mannheim, Germany.
| | - Michael Keese
- Department of Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. .,European Center of Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. .,Department for General and Visceral Surgery, Theresienkrankenhaus Mannheim, Mannheim, Germany. .,Department of Surgery, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68161, Mannheim, Germany.
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32
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Shuster-Hyman H, Siddiqui F, Gallagher D, Gauthier-Fisher A, Librach CL. Time course and mechanistic analysis of human umbilical cord perivascular cell mitigation of lipopolysaccharide-induced systemic and neurological inflammation. Cytotherapy 2023; 25:125-137. [PMID: 36473795 DOI: 10.1016/j.jcyt.2022.10.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 10/11/2022] [Accepted: 10/20/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND AIMS Because of their potent immunomodulatory and anti-inflammatory properties, mesenchymal stromal cells are a major focus in the field of stem cell therapy. However, the precise mechanisms underlying this are not entirely understood. Human umbilical cord perivascular cells (HUCPVCs) are a promising cell therapy candidate. This study was designed to evaluate the time course and mechanisms by which HUCPVCs mitigate lipopolysaccharide (LPS)-induced systemic and neurological inflammation in immunocompetent mice. To explore the underlying mechanisms, the authors investigated the biodistribution and fate of HUCPVCs. METHODS Male C57BL/6 mice were randomly allocated to four groups: control, LPS, HUCPVCs or LPS + HUCPVCs. Quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and cytokine arrays were used to assess changes in pro-inflammatory mediators systemically and in the brain. Depressive-like behavioral changes were evaluated via a forced swim test. Quantum dot (qDot) labeling and immunohistochemistry were used to assess the biodistribution and fate of HUCPVCs and interactions with recipient innate immune cells. RESULTS A single intravenously delivered dose of HUCPVCs significantly reduced the systemic inflammation induced by LPS within the first 24 h after administration. HUCPVC treatment abrogated the upregulated expression of pro-inflammatory genes in the hippocampus and cortex and attenuated depressive-like behavior induced by LPS treatment. Biodistribution analysis revealed that HUCPVC-derived qDots rapidly accumulated in the lungs and demonstrated limited in vivo persistence. Furthermore, qDot signals were associated with major recipient innate immune cells and promoted a shift in macrophages toward a regulatory phenotype in the lungs. CONCLUSIONS Overall, this study demonstrates that HUCPVCs can successfully reduce systemic and neurological inflammation induced by LPS within the first 24 h after administration. Biodistribution and fate analyses suggest a critical role for the innate immune system in the HUCPVC-based immunomodulation mechanism.
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Affiliation(s)
- Hannah Shuster-Hyman
- CReATe Fertility Center, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | | | | | | | - Clifford L Librach
- CReATe Fertility Center, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
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Ma M, Cui G, Liu Y, Tang Y, Lu X, Yue C, Zhang X. Mesenchymal stem cell-derived extracellular vesicles, osteoimmunology and orthopedic diseases. PeerJ 2023; 11:e14677. [PMID: 36710868 PMCID: PMC9881470 DOI: 10.7717/peerj.14677] [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: 08/29/2022] [Accepted: 12/12/2022] [Indexed: 01/26/2023] Open
Abstract
Mesenchymal stem cells (MSCs) play an important role in tissue healing and regenerative medicine due to their self-renewal and multi-directional differentiation properties. MSCs exert their therapeutic effects mainly via the paracrine pathway, which involves the secretion of extracellular vesicles (EVs). EVs have a high drug loading capacity and can transport various molecules, such as proteins, nucleic acids, and lipids, that can modify the course of diverse diseases. Due to their ability to maintain the therapeutic effects of their parent cells, MSC-derived EVs have emerged as a promising, safe cell-free treatment approach for tissue regeneration. With advances in inflammation research and emergence of the field of osteoimmunology, evidence has accumulated pointing to the role of inflammatory and osteoimmunological processes in the occurrence and progression of orthopedic diseases. Several studies have shown that MSC-derived EVs participate in bone regeneration and the pathophysiology of orthopedic diseases by regulating the inflammatory environment, enhancing angiogenesis, and promoting the differentiation and proliferation of osteoblasts and osteoclasts. In this review, we summarize recent advances in the application and functions of MSC-derived EVs as potential therapies against orthopedic diseases, including osteoarthritis, intervertebral disc degeneration, osteoporosis and osteonecrosis.
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Affiliation(s)
- Maoxiao Ma
- Department of Orthopedics, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, Henan, China
| | - Guofeng Cui
- Department of Orthopedics, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan, China
| | - Youwen Liu
- Department of Orthopedics, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, Henan, China
| | - Yanfeng Tang
- Department of Orthopedics, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, Henan, China
| | - Xiaoshuai Lu
- Department of Orthopedics, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, Henan, China
| | - Chen Yue
- Department of Orthopedics, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, Henan, China
| | - Xue Zhang
- Department of Orthopedics, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Hospital of Henan Province, Luoyang, Henan, China
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Martí‐Chillón G, Muntión S, Preciado S, Osugui L, Navarro‐Bailón A, González‐Robledo J, Sagredo V, Blanco JF, Sánchez‐Guijo F. Therapeutic potential of mesenchymal stromal/stem cells in critical-care patients with systemic inflammatory response syndrome. Clin Transl Med 2023; 13:e1163. [PMID: 36588089 PMCID: PMC9806020 DOI: 10.1002/ctm2.1163] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 12/15/2022] [Accepted: 12/19/2022] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Despite notable advances in the support and treatment of patients admitted to the intensive care unit (ICU), the management of those who develop a systemic inflammatory response syndrome (SIRS) still constitutes an unmet medical need. MAIN BODY Both the initial injury (trauma, pancreatitis, infections) and the derived uncontrolled response promote a hyperinflammatory status that leads to systemic hypotension, tissue hypoperfusion and multiple organ failure. Mesenchymal stromal/stem cells (MSCs) are emerging as a potential therapy for severe ICU patients due to their potent immunomodulatory, anti-inflammatory, regenerative and systemic homeostasis-regulating properties. MSCs have demonstrated clinical benefits in several inflammatory-based diseases, but their role in SIRS needs to be further explored. CONCLUSION In the current review, after briefly overviewing SIRS physiopathology, we explore the potential mechanisms why MSC therapy could aid in the recovery of this condition and the pre-clinical and early clinical evidence generated to date.
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Affiliation(s)
| | - Sandra Muntión
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- RICORS TERAVISCIIIMadridSpain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y LeónSalamancaSpain
| | - Silvia Preciado
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- RICORS TERAVISCIIIMadridSpain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y LeónSalamancaSpain
| | - Lika Osugui
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y LeónSalamancaSpain
| | - Almudena Navarro‐Bailón
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- RICORS TERAVISCIIIMadridSpain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y LeónSalamancaSpain
| | - Javier González‐Robledo
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- Department of MedicineUniversity of SalamancaSalamancaSpain
| | | | - Juan F. Blanco
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y LeónSalamancaSpain
- Department of SurgeryUniversity of SalamancaSalamancaSpain
| | - Fermín Sánchez‐Guijo
- IBSAL‐University Hospital of SalamancaSalamancaSpain
- Department of MedicineUniversity of SalamancaSalamancaSpain
- RICORS TERAVISCIIIMadridSpain
- Regenerative Medicine and Cellular Therapy Network Center of Castilla y LeónSalamancaSpain
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Niebergall-Roth E, Frank NY, Ganss C, Frank MH, Kluth MA. Skin-Derived ABCB5 + Mesenchymal Stem Cells for High-Medical-Need Inflammatory Diseases: From Discovery to Entering Clinical Routine. Int J Mol Sci 2022; 24:66. [PMID: 36613507 PMCID: PMC9820160 DOI: 10.3390/ijms24010066] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/16/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022] Open
Abstract
The ATP-binding cassette superfamily member ABCB5 identifies a subset of skin-resident mesenchymal stem cells (MSCs) that exhibit potent immunomodulatory and wound healing-promoting capacities along with superior homing ability. The ABCB5+ MSCs can be easily accessed from discarded skin samples, expanded, and delivered as a highly homogenous medicinal product with standardized potency. A range of preclinical studies has suggested therapeutic efficacy of ABCB5+ MSCs in a variety of currently uncurable skin and non-skin inflammatory diseases, which has been substantiated thus far by distinct clinical trials in chronic skin wounds or recessive dystrophic epidermolysis bullosa. Therefore, skin-derived ABCB5+ MSCs have the potential to provide a breakthrough at the forefront of MSC-based therapies striving to fulfill current unmet medical needs. The most recent milestones in this regard are the approval of a phase III pivotal trial of ABCB5+ MSCs for treatment of recessive dystrophic and junctional epidermolysis bullosa by the US Food and Drug Administration, and national market access of ABCB5+ MSCs (AMESANAR®) for therapy-refractory chronic venous ulcers under the national hospital exemption pathway in Germany.
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Affiliation(s)
| | - Natasha Y. Frank
- Department of Medicine, VA Boston Healthcare System, Boston, MA 02132, USA
- Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
- Transplant Research Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Christoph Ganss
- TICEBA GmbH, 69120 Heidelberg, Germany
- RHEACELL GmbH & Co. KG, 69120 Heidelberg, Germany
| | - Markus H. Frank
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
- Transplant Research Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- School of Medical and Health Sciences, Edith Cowan University, Perth 6027, Australia
| | - Mark A. Kluth
- TICEBA GmbH, 69120 Heidelberg, Germany
- RHEACELL GmbH & Co. KG, 69120 Heidelberg, Germany
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Ragni E, Perucca Orfei C, De Luca P, Libonati F, de Girolamo L. Tissue-Protective and Anti-Inflammatory Landmark of PRP-Treated Mesenchymal Stromal Cells Secretome for Osteoarthritis. Int J Mol Sci 2022; 23:ijms232415908. [PMID: 36555578 PMCID: PMC9788137 DOI: 10.3390/ijms232415908] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/07/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022] Open
Abstract
Bone-marrow-mesenchymal-stromal-cells (BMSCs)- and platelet-rich-plasma (PRP)-based therapies have shown potential for treating osteoarthritis (OA). Recently, the combination of these two approaches was proposed, with results that overcame those observed with the separate treatments, indicating a possible role of PRP in ameliorating BMSCs' regenerative properties. Since a molecular fingerprint of BMSCs cultivated in the presence of PRP is missing, the aim of this study was to characterize the secretome in terms of soluble factors and extracellular-vesicle (EV)-embedded miRNAs from the perspective of tissues, pathways, and molecules which frame OA pathology. One hundred and five soluble factors and one hundred eighty-four EV-miRNAs were identified in the PRP-treated BMSCs' secretome, respectively. Several soluble factors were related to the migration of OA-related immune cells, suggesting the capacity of BMSCs to attract lympho-, mono-, and granulocytes and modulate their inflammatory status. Accordingly, several EV-miRNAs had an immunomodulating role at both the single-factor and cell level, together with the ability to target OA-characterizing extracellular-matrix-degrading enzymes and cartilage destruction pathways. Overall, anti-inflammatory and protective signals far exceeded inflammation and destruction cues for cartilage, macrophages, and T cells. This study demonstrates that BMSCs cultivated in the presence of PRP release therapeutic molecules and give molecular ground for the use of this combined and innovative therapy for OA treatment.
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Hua C, Chen S, Cheng H. Therapeutic potential of mesenchymal stem cells for refractory inflammatory and immune skin diseases. Hum Vaccin Immunother 2022; 18:2144667. [PMID: 36382475 PMCID: PMC9746473 DOI: 10.1080/21645515.2022.2144667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Inflammatory and immunological skin diseases such as psoriasis, systemic sclerosis, dermatomyositis and atopic dermatitis, whose abnormal skin manifestations not only affected life quality but also caused social discrimination, have been wildly concerned. Complex variables such as hereditary predisposition, racial differences, age and gender can influence the prevalence and therapeutic options. The population of patients with unsatisfactory curative effects under current therapies is growing, it's advisable to seek novel and advanced therapies that are less likely to cause systemic damage. Mesenchymal stem cells (MSCs) have been proven with therapeutic benefits in tissue regeneration, self-renewal and differentiation abilities when treating refractory skin disorders in preclinical and clinical studies. Here we highlighted the immune modulation and inflammation suppression of MSCs in skin diseases, summarized current studies, research progress and related clinical trials, hoping to strengthen the confidence of promising MSCs therapy in future clinical application.
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Affiliation(s)
- Chunting Hua
- Department of Dermatology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Siji Chen
- Department of Dermatology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hao Cheng
- Department of Dermatology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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Yudintceva N, Mikhailova N, Fedorov V, Samochernych K, Vinogradova T, Muraviov A, Shevtsov M. Mesenchymal Stem Cells and MSCs-Derived Extracellular Vesicles in Infectious Diseases: From Basic Research to Clinical Practice. Bioengineering (Basel) 2022; 9:662. [PMID: 36354573 PMCID: PMC9687734 DOI: 10.3390/bioengineering9110662] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/30/2022] [Accepted: 11/04/2022] [Indexed: 08/10/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are attractive in various fields of regenerative medicine due to their therapeutic potential and complex unique properties. Basic stem cell research and the global COVID-19 pandemic have given impetus to the development of cell therapy for infectious diseases. The aim of this review was to systematize scientific data on the applications of mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) in the combined treatment of infectious diseases. Application of MSCs and MSC-EVs in the treatment of infectious diseases has immunomodulatory, anti-inflammatory, and antibacterial effects, and also promotes the restoration of the epithelium and stimulates tissue regeneration. The use of MSC-EVs is a promising cell-free treatment strategy that allows solving the problems associated with the safety of cell therapy and increasing its effectiveness. In this review, experimental data and clinical trials based on MSCs and MSC-EVs for the treatment of infectious diseases are presented. MSCs and MSC-EVs can be a promising tool for the treatment of various infectious diseases, particularly in combination with antiviral drugs. Employment of MSC-derived EVs represents a more promising strategy for cell-free treatment, demonstrating a high therapeutic potential in preclinical studies.
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Affiliation(s)
- Natalia Yudintceva
- Institute of Cytology of the Russian Academy of Sciences (RAS), St. Petersburg 194064, Russia
- Personalized Medicine Centre, Almazov National Medical Research Centre, St. Petersburg 197341, Russia
| | - Natalia Mikhailova
- Institute of Cytology of the Russian Academy of Sciences (RAS), St. Petersburg 194064, Russia
| | - Viacheslav Fedorov
- Personalized Medicine Centre, Almazov National Medical Research Centre, St. Petersburg 197341, Russia
| | - Konstantin Samochernych
- Personalized Medicine Centre, Almazov National Medical Research Centre, St. Petersburg 197341, Russia
| | - Tatiana Vinogradova
- Saint-Petersburg State Research Institute of Phthisiopulmonology of the Ministry of Health of the Russian Federation, St. Petersburg 191036, Russia
| | - Alexandr Muraviov
- Saint-Petersburg State Research Institute of Phthisiopulmonology of the Ministry of Health of the Russian Federation, St. Petersburg 191036, Russia
| | - Maxim Shevtsov
- Institute of Cytology of the Russian Academy of Sciences (RAS), St. Petersburg 194064, Russia
- Personalized Medicine Centre, Almazov National Medical Research Centre, St. Petersburg 197341, Russia
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Kerstan A, Dieter K, Niebergall-Roth E, Klingele S, Jünger M, Hasslacher C, Daeschlein G, Stemler L, Meyer-Pannwitt U, Schubert K, Klausmann G, Raab T, Goebeler M, Kraft K, Esterlechner J, Schröder HM, Sadeghi S, Ballikaya S, Gasser M, Waaga-Gasser AM, Murphy GF, Orgill DP, Frank NY, Ganss C, Scharffetter-Kochanek K, Frank MH, Kluth MA. Translational development of ABCB5 + dermal mesenchymal stem cells for therapeutic induction of angiogenesis in non-healing diabetic foot ulcers. Stem Cell Res Ther 2022; 13:455. [PMID: 36064604 PMCID: PMC9444095 DOI: 10.1186/s13287-022-03156-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 06/25/2022] [Indexed: 11/15/2022] Open
Abstract
Background While rapid healing of diabetic foot ulcers (DFUs) is highly desirable to avoid infections, amputations and life-threatening complications, DFUs often respond poorly to standard treatment. GMP-manufactured skin-derived ABCB5+ mesenchymal stem cells (MSCs) might provide a new adjunctive DFU treatment, based on their remarkable skin wound homing and engraftment potential, their ability to adaptively respond to inflammatory signals, and their wound healing-promoting efficacy in mouse wound models and human chronic venous ulcers. Methods The angiogenic potential of ABCB5+ MSCs was characterized with respect to angiogenic factor expression at the mRNA and protein level, in vitro endothelial trans-differentiation and tube formation potential, and perfusion-restoring capacity in a mouse hindlimb ischemia model. Finally, the efficacy and safety of ABCB5+ MSCs for topical adjunctive treatment of chronic, standard therapy-refractory, neuropathic plantar DFUs were assessed in an open-label single-arm clinical trial. Results Hypoxic incubation of ABCB5+ MSCs led to posttranslational stabilization of the hypoxia-inducible transcription factor 1α (HIF-1α) and upregulation of HIF-1α mRNA levels. HIF-1α pathway activation was accompanied by upregulation of vascular endothelial growth factor (VEGF) transcription and increase in VEGF protein secretion. Upon culture in growth factor-supplemented medium, ABCB5+ MSCs expressed the endothelial-lineage marker CD31, and after seeding on gel matrix, ABCB5+ MSCs demonstrated formation of capillary-like structures comparable with human umbilical vein endothelial cells. Intramuscularly injected ABCB5+ MSCs to mice with surgically induced hindlimb ischemia accelerated perfusion recovery as measured by laser Doppler blood perfusion imaging and enhanced capillary proliferation and vascularization in the ischemic muscles. Adjunctive topical application of ABCB5+ MSCs onto therapy-refractory DFUs elicited median wound surface area reductions from baseline of 59% (full analysis set, n = 23), 64% (per-protocol set, n = 20) and 67% (subgroup of responders, n = 17) at week 12, while no treatment-related adverse events were observed. Conclusions The present observations identify GMP-manufactured ABCB5+ dermal MSCs as a potential, safe candidate for adjunctive therapy of otherwise incurable DFUs and justify the conduct of a larger, randomized controlled trial to validate the clinical efficacy. Trial registration: ClinicalTrials.gov, NCT03267784, Registered 30 August 2017, https://clinicaltrials.gov/ct2/show/NCT03267784 Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03156-9.
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Affiliation(s)
- Andreas Kerstan
- Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany
| | | | | | - Sabrina Klingele
- TICEBA GmbH, Im Neuenheimer Feld 517, 69120, Heidelberg, Germany
| | - Michael Jünger
- Department of Dermatology, University Hospital Greifswald, Greifswald, Germany
| | | | - Georg Daeschlein
- Department of Dermatology, University Hospital Greifswald, Greifswald, Germany.,Clinic of Dermatology, Immunology and Allergology, Medical University Brandenburg "Theodor Fontane" Medical Center Dessau, Dessau, Germany
| | - Lutz Stemler
- Diabetologikum DDG Ludwigshafen, Ludwigshafen, Germany
| | | | | | | | | | - Matthias Goebeler
- Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany
| | | | | | | | - Samar Sadeghi
- TICEBA GmbH, Im Neuenheimer Feld 517, 69120, Heidelberg, Germany
| | - Seda Ballikaya
- TICEBA GmbH, Im Neuenheimer Feld 517, 69120, Heidelberg, Germany
| | - Martin Gasser
- Department of Surgery, University Hospital Würzburg, Würzburg, Germany
| | - Ana M Waaga-Gasser
- Department of Surgery, University Hospital Würzburg, Würzburg, Germany.,Division of Renal (Kidney) Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - George F Murphy
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Dennis P Orgill
- Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Natasha Y Frank
- Department of Medicine, VA Boston Healthcare System, Boston, MA, USA.,Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.,Transplant Research Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.,Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
| | - Christoph Ganss
- RHEACELL GmbH & Co. KG, Heidelberg, Germany.,TICEBA GmbH, Im Neuenheimer Feld 517, 69120, Heidelberg, Germany
| | | | - Markus H Frank
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.,Transplant Research Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.,Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.,School of Medical and Health Sciences, Edith Cowan University, Perth, Australia
| | - Mark A Kluth
- RHEACELL GmbH & Co. KG, Heidelberg, Germany. .,TICEBA GmbH, Im Neuenheimer Feld 517, 69120, Heidelberg, Germany.
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40
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Zheng Z, Xu Y, Shi Y, Shao C. Neutrophils in the tumor microenvironment and their functional modulation by mesenchymal stromal cells. Cell Immunol 2022; 379:104576. [DOI: 10.1016/j.cellimm.2022.104576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 11/28/2022]
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Klein L, Ophelders DR, van den Hove D, Damoiseaux M, Rutten BP, Reutelingsperger CP, Schurgers LJ, Wolfs TG. Prenatal administration of multipotent adult progenitor cells modulates the systemic and cerebral immune response in an ovine model of chorioamnionitis. Brain Behav Immun Health 2022; 23:100458. [PMID: 35647567 PMCID: PMC9136278 DOI: 10.1016/j.bbih.2022.100458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/17/2022] [Accepted: 03/31/2022] [Indexed: 11/30/2022] Open
Abstract
Systemic and cerebral inflammation following antenatal infection (e.g. chorioamnionitis) and dysregulation of the blood brain barrier (BBB) are major risk factors for abnormal neonatal brain development. Administration of multipotent adult progenitor cells (MAPCs) represents an interesting pharmacological strategy as modulator of the peripheral and cerebral immune response and protector of BBB integrity. We studied the immunomodulatory and protective cerebrovascular potential of prenatally administered MAPCs in a preclinical ovine model for antenatal inflammation. Ovine fetuses were intra-amniotically (i.a.) exposed to lipopolysaccharide (LPS) or saline at gestational day 125, followed by the intravenous administration of 1*107 MAPCs or saline at gestational day 127. Circulating inflammation markers were measured. Fetal brains were examined immuno-histochemically post-mortem at gestational day 132. Fetal plasma IL-6 levels were elevated significantly 24 h after LPS administration. In utero systemic MAPC treatment after LPS exposure increased Annexin A1 (ANXA1) expression in the cerebrovascular endothelium, indicating enforcement of BBB integrity, and increased the number of leukocytes at brain barriers throughout the brain. Further characterisation of brain barrier-associated leukocytes showed that monocyte/choroid plexus macrophage (IBA-1+/CD206+) and neutrophil (MPO+) populations predominantly contributed to the LPS-MAPC-induced increase of CD45+cells. In the choroid plexus, the percentage of leukocytes expressing the proresolving mediator ANXA1 tended to be decreased after LPS-induced antenatal inflammation, an effect reversed by systemic MAPC treatment. Accordingly, expression levels of ANXA1 per leukocyte were decreased after LPS and restored after subsequent MAPC treatment. Increased expression of ANXA1 by the cerebrovasculature and immune cells at brain barriers following MAPC treatment in an infectious setting indicate a MAPC driven early defence mechanism to protect the neonatal brain against infection-driven inflammation and potential additional pro-inflammatory insults in the neonatal period.
MAPCs administered systemically enhance the brain directed immune response in an inflammation dependent manner in preterm fetuses. Annexin A1 expression is increased in cerebrovasculature and immune cells at brain barriers when MAPCs were i.v. administered in the infectious setting. MAPCs potentially protect the neonatal brain by enforcing the blood brain barrier and modulating inflammation.
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Affiliation(s)
- Luise Klein
- School for Oncology and Reproduction (GROW), Maastricht University, Maastricht, the Netherlands
- Department of Pediatrics, Maastricht University, Maastricht, the Netherlands
- School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, the Netherlands
| | - Daan R.M.G. Ophelders
- School for Oncology and Reproduction (GROW), Maastricht University, Maastricht, the Netherlands
- Department of Pediatrics, Maastricht University, Maastricht, the Netherlands
| | - Daniel van den Hove
- School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, the Netherlands
- Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany
- Department of Psychiatry and Neuropsychology, European Graduate School of Neuroscience (EURON), Faculty of Health, Medicine and Life Sciences (FHML), Maastricht University, Maastricht, the Netherlands
| | - Maurits Damoiseaux
- School for Oncology and Reproduction (GROW), Maastricht University, Maastricht, the Netherlands
- Department of Pediatrics, Maastricht University, Maastricht, the Netherlands
| | - Bart P.F. Rutten
- School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, the Netherlands
- Department of Psychiatry and Neuropsychology, European Graduate School of Neuroscience (EURON), Faculty of Health, Medicine and Life Sciences (FHML), Maastricht University, Maastricht, the Netherlands
| | - Chris P.M. Reutelingsperger
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands
| | - Leon J. Schurgers
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands
| | - Tim G.A.M. Wolfs
- School for Oncology and Reproduction (GROW), Maastricht University, Maastricht, the Netherlands
- Department of Pediatrics, Maastricht University, Maastricht, the Netherlands
- Corresponding author. School for Oncology and Reproduction (GROW), Maastricht University, Maastricht, the Netherlands.
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Tanabe S, O’Brien J, Tollefsen KE, Kim Y, Chauhan V, Yauk C, Huliganga E, Rudel RA, Kay JE, Helm JS, Beaton D, Filipovska J, Sovadinova I, Garcia-Reyero N, Mally A, Poulsen SS, Delrue N, Fritsche E, Luettich K, La Rocca C, Yepiskoposyan H, Klose J, Danielsen PH, Esterhuizen M, Jacobsen NR, Vogel U, Gant TW, Choi I, FitzGerald R. Reactive Oxygen Species in the Adverse Outcome Pathway Framework: Toward Creation of Harmonized Consensus Key Events. FRONTIERS IN TOXICOLOGY 2022; 4:887135. [PMID: 35875696 PMCID: PMC9298159 DOI: 10.3389/ftox.2022.887135] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 06/13/2022] [Indexed: 02/05/2023] Open
Abstract
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are formed as a result of natural cellular processes, intracellular signaling, or as adverse responses associated with diseases or exposure to oxidizing chemical and non-chemical stressors. The action of ROS and RNS, collectively referred to as reactive oxygen and nitrogen species (RONS), has recently become highly relevant in a number of adverse outcome pathways (AOPs) that capture, organize, evaluate and portray causal relationships pertinent to adversity or disease progression. RONS can potentially act as a key event (KE) in the cascade of responses leading to an adverse outcome (AO) within such AOPs, but are also known to modulate responses of events along the AOP continuum without being an AOP event itself. A substantial discussion has therefore been undertaken in a series of workshops named "Mystery or ROS" to elucidate the role of RONS in disease and adverse effects associated with exposure to stressors such as nanoparticles, chemical, and ionizing and non-ionizing radiation. This review introduces the background for RONS production, reflects on the direct and indirect effects of RONS, addresses the diversity of terminology used in different fields of research, and provides guidance for developing a harmonized approach for defining a common event terminology within the AOP developer community.
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Affiliation(s)
- Shihori Tanabe
- Division of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki, Japan
| | - Jason O’Brien
- Wildlife Toxicology Research Section, Environment and Climate Change Canada, Toronto, ON, Canada
| | - Knut Erik Tollefsen
- Norwegian Institute for Water Research (NIVA), Oslo, Norway
- Norwegian University of Life Sciences (NMBU), Ås, Norway
- Centre for Environmental Radioactivity, Norwegian University of Life Sciences (NMBU), Ås, Norway
| | - Youngjun Kim
- Korea Institute of Science and Technology (KIST) Europe, Saarbrücken, Germany
| | | | | | | | | | | | | | | | | | - Iva Sovadinova
- RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Natalia Garcia-Reyero
- U.S. Army Engineer Research and Development Center (ERDC), Vicksburg, MS, United States
| | - Angela Mally
- Department of Toxicology, University of Würzburg, Würzburg, Germany
| | - Sarah Søs Poulsen
- National Research Centre for the Working Environment, Copenhagen, Denmark
| | - Nathalie Delrue
- Organisation for Economic Co-operation and Development (OECD), Paris, France
| | - Ellen Fritsche
- Group of Alternative Method Development for Environmental Toxicity Testing, IUF—Leibniz-Research Institute for Environmental Medicine, Duesseldorf, Germany
| | - Karsta Luettich
- Philip Morris International R&D, Philip Morris Products SA, Neuchatel, Switzerland
| | - Cinzia La Rocca
- Center for Gender-specific Medicine, Italian National Institute of Health, Rome, Italy
| | - Hasmik Yepiskoposyan
- Philip Morris International R&D, Philip Morris Products SA, Neuchatel, Switzerland
| | - Jördis Klose
- Group of Alternative Method Development for Environmental Toxicity Testing, IUF—Leibniz-Research Institute for Environmental Medicine, Duesseldorf, Germany
| | | | - Maranda Esterhuizen
- University of Helsinki, Ecosystems and Environment Research Programme, Faculty of Biological and Environmental Sciences, Lahti, Finland, and Helsinki Institute of Sustainability Science (HELSUS), Helsinki, Finland
| | | | - Ulla Vogel
- National Research Centre for the Working Environment, Copenhagen, Denmark
| | - Timothy W. Gant
- UK Health Security Agency, Public Health England, London, United Kingdom
| | - Ian Choi
- Korea Institute of Science and Technology (KIST) Europe, Saarbrücken, Germany
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Martin KE, Kalelkar PP, Coronel MM, Theriault HS, Schneider RS, García AJ. Host type 2 immune response to xenogeneic serum components impairs biomaterial-directed osteo-regenerative therapies. Biomaterials 2022; 286:121601. [PMID: 35660823 PMCID: PMC11458135 DOI: 10.1016/j.biomaterials.2022.121601] [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: 03/18/2022] [Revised: 05/20/2022] [Accepted: 05/22/2022] [Indexed: 11/21/2022]
Abstract
The transformative potential of cells as therapeutic agents is being realized in a wide range of applications, from regenerative medicine to cancer therapy to autoimmune disorders. The majority of these therapies require ex vivo expansion of the cellular product, often utilizing fetal bovine serum (FBS) in the culture media. However, the impact of residual FBS on immune responses to cell therapies and the resulting cell therapy outcomes remains unclear. Here, we show that hydrogel-delivered FBS elicits a robust type 2 immune response characterized by infiltration of eosinophils and CD4+ T cells. Host secretion of cytokines associated with type 2 immunity, including IL-4, IL-5, and IL-13, is also increased in FBS-containing hydrogels. We demonstrate that the immune response to xenogeneic serum components dominates the local environment and masks the immunomodulatory effects of biomaterial-delivered mesenchymal stromal/stem cells. Importantly, delivery of relatively small amounts of FBS (3.2% by volume) within BMP-2-containing biomaterial constructs dramatically reduces the ability of these constructs to promote de novo bone formation in a radial defect model in immunocompetent mice. These results urge caution when interpreting the immunological and tissue repair outcomes in immunocompetent pre-clinical models from cells and biomaterial constructs that have come in contact with xenogeneic serum components.
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Affiliation(s)
- Karen E Martin
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Pranav P Kalelkar
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - María M Coronel
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Hannah S Theriault
- Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Rebecca S Schneider
- Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA; School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Andrés J García
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA.
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Mittal SK, Cho W, Elbasiony E, Guan Y, Foulsham W, Chauhan SK. Mesenchymal stem cells augment regulatory T cell function via CD80-mediated interactions and promote allograft survival. Am J Transplant 2022; 22:1564-1577. [PMID: 35170213 PMCID: PMC11261724 DOI: 10.1111/ajt.17001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 01/25/2022] [Accepted: 02/09/2022] [Indexed: 02/05/2023]
Abstract
Mesenchymal stem cells (MSCs) and regulatory T cells (Tregs) both have been shown to modulate the alloimmune response and promote transplant survival. Mounting evidence suggests that MSCs augment Treg function, but the mechanisms underlying this phenomenon have not been fully deciphered. Here, we identified that MSCs express substantial levels of CD80 and evaluated its immunoregulatory function using in vivo and in vitro experiments. Our in vitro culture assays demonstrated that MSCs induce expression of FoxP3 in Tregs in a contact-dependent manner, and the blockade of CD80 abrogates this FoxP3 induction and Treg-mediated suppression of T cell proliferation. Moreover, supplementation of soluble CD80 significantly upregulated FoxP3 expression. Using a well-characterized murine model of corneal transplantation, we show that silencing CD80 in MSCs diminishes the capacity of MSCs to promote selective graft infiltration of Tregs, promote FoxP3 expression and upregulate suppressive function of Tregs. Consequently, MSCs, following CD80 knockdown, failed to promote corneal allograft survival.
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Affiliation(s)
- Sharad K Mittal
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA
| | - WonKyung Cho
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA
| | - Elsayed Elbasiony
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA
| | - Yilin Guan
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA
| | - William Foulsham
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA
| | - Sunil K Chauhan
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA
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45
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Extracellular vesicles derived from mesenchymal stromal cells as nanotherapeutics for liver ischaemia–reperfusion injury by transferring mitochondria to modulate the formation of neutrophil extracellular traps'. Biomaterials 2022; 284:121486. [PMID: 35447404 DOI: 10.1016/j.biomaterials.2022.121486] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 02/08/2022] [Accepted: 03/23/2022] [Indexed: 12/23/2022]
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Alvites R, Branquinho M, Sousa AC, Lopes B, Sousa P, Maurício AC. Mesenchymal Stem/Stromal Cells and Their Paracrine Activity-Immunomodulation Mechanisms and How to Influence the Therapeutic Potential. Pharmaceutics 2022; 14:381. [PMID: 35214113 PMCID: PMC8875256 DOI: 10.3390/pharmaceutics14020381] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 01/31/2022] [Accepted: 02/04/2022] [Indexed: 02/07/2023] Open
Abstract
With high clinical interest to be applied in regenerative medicine, Mesenchymal Stem/Stromal Cells have been widely studied due to their multipotency, wide distribution, and relative ease of isolation and expansion in vitro. Their remarkable biological characteristics and high immunomodulatory influence have opened doors to the application of MSCs in many clinical settings. The therapeutic influence of these cells and the interaction with the immune system seems to occur both directly and through a paracrine route, with the production and secretion of soluble factors and extracellular vesicles. The complex mechanisms through which this influence takes place is not fully understood, but several functional manipulation techniques, such as cell engineering, priming, and preconditioning, have been developed. In this review, the knowledge about the immunoregulatory and immunomodulatory capacity of MSCs and their secretion products is revisited, with a special focus on the phenomena of migration and homing, direct cell action and paracrine activity. The techniques for homing improvement, cell modulation and conditioning prior to the application of paracrine factors were also explored. Finally, multiple assays where different approaches were applied with varying success were used as examples to justify their exploration.
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Affiliation(s)
- Rui Alvites
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Mariana Branquinho
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Ana C. Sousa
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Bruna Lopes
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Patrícia Sousa
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
| | - Ana Colette Maurício
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA) da Universidade do Porto, Praça Gomes Teixeira, Apartado 55142, 4051-401 Porto, Portugal; (R.A.); (M.B.); (A.C.S.); (B.L.); (P.S.)
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, nº 228, 4050-313 Porto, Portugal
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Yoon HS, Kim HY, Cho KA, Kim YH, Woo SY, Kim HS, Kang JL, Ryu KH, Park JW. Procollagen C-Endopeptidase Enhancer 2 Secreted by Tonsil-Derived Mesenchymal Stem Cells Increases the Oxidative Burst of Promyelocytic HL-60 Cells. BIOLOGY 2022; 11:biology11020255. [PMID: 35205121 PMCID: PMC8869569 DOI: 10.3390/biology11020255] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 01/25/2022] [Accepted: 01/31/2022] [Indexed: 12/19/2022]
Abstract
Simple Summary Tonsil-derived mesenchymal stem cells (TMSCs) improved the reactive oxygen species (ROS) production in human promyelocytic leukaemia cells (HL-60) differentiated into neutrophil-like cells (dHL-60). TMSC-induced enhancement of ROS generation in dHL-60 cells was different depending on the TMSC donor. Comparison of RNA-sequencing data between high and low potentiating TMSC groups for ROS generation in dHL-60 cells showed elevated expressions of four genes: secreted frizzled-related protein 4, mesenteric estrogen-dependent adipogenesis, microfibrillar associated protein 5, and procollagen C-endopeptidase enhancer 2 (PCOLCE2). Real-time PCR and Western blotting confirmed high levels of PCOLCE2 in the high potentiating TMSC group for ROS generation in dHL-60 cells. In addition, knockdown of PCOLCE2 in TMSCs reduced the enhancing efficacy of TMSCs regarding ROS generation in dHL-60 cells. Finally, treatment of recombinant PCOLCE2 protein augmented ROS production in dHL-60 cells with concomitant increases of NADPH oxidase (NOX) 3, NOX4, NOX5, and dual oxidase 2. Taken together, this study showed that PCOLCE2 levels in TMSCs could be used to select TMSCs with the high potentiating ability for ROS generation in neutrophils, and both TMSCs and PCOLCE2 may have the potential to enhance a frontline defence by increasing the efficiency of ROS generation in neutrophils. Abstract Reactive oxygen species (ROS) generated by neutrophils provide a frontline defence against invading pathogens. We investigated the supportive effect of tonsil-derived mesenchymal stem cells (TMSCs) on ROS generation from neutrophils using promyelocytic HL-60 cells. Methods: Differentiated HL-60 (dHL-60) cells were cocultured with TMSCs isolated from 25 independent donors, and ROS generation in dHL-60 cells was measured using luminescence. RNA sequencing and real-time PCR were performed to identify the candidate genes of TMSCs involved in augmenting the oxidative burst of dHL-60 cells. Transcriptome analysis of TMSCs derived from 25 independent donors revealed high levels of procollagen C-endopeptidase enhancer 2 (PCOLCE2) in TMSCs, which were highly effective in potentiating ROS generation in dHL-60 cells. In addition, PCOLCE2 knockdown in TMSCs abrogated TMSC-induced enhancement of ROS production in dHL-60 cells, indicating that TMSCs increased the oxidative burst in dHL-60 cells via PCOLCE2. Furthermore, the direct addition of recombinant PCOLCE2 protein increased ROS production in dHL-60 cells. These results suggest that PCOLCE2 secreted by TMSCs may be used as a therapeutic candidate to enhance host defences by increasing neutrophil oxidative bursts. PCOLCE2 levels in TMSCs could be used as a marker to select TMSCs exhibiting high efficacy for enhancing neutrophil oxidative bursts.
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Affiliation(s)
- Hee-Soo Yoon
- Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul 07084, Korea; (H.-S.Y.); (H.-Y.K.)
| | - Hee-Yeon Kim
- Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul 07084, Korea; (H.-S.Y.); (H.-Y.K.)
| | - Kyung-Ah Cho
- Department of Microbiology, College of Medicine, Ewha Womans University, Seoul 07084, Korea; (K.-A.C.); (Y.-H.K.); (S.-Y.W.)
| | - Yu-Hee Kim
- Department of Microbiology, College of Medicine, Ewha Womans University, Seoul 07084, Korea; (K.-A.C.); (Y.-H.K.); (S.-Y.W.)
| | - So-Youn Woo
- Department of Microbiology, College of Medicine, Ewha Womans University, Seoul 07084, Korea; (K.-A.C.); (Y.-H.K.); (S.-Y.W.)
| | - Han-Su Kim
- Department of Otorhinolaryngology, College of Medicine, Ewha Womans University, Seoul 07985, Korea;
| | - Jihee-Lee Kang
- Department of Physiology, College of Medicine, Ewha Womans University, Seoul 07084, Korea;
- Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, Seoul 07084, Korea
| | - Kyung-Ha Ryu
- Department of Pediatrics, College of Medicine, Ewha Womans University, Seoul 07084, Korea
- Correspondence: (K.-H.R.); (J.-W.P.); Tel.: +82-2-2653-3718 (K.-H.R.); +82-2-6986-6201 (J.-W.P.)
| | - Joo-Won Park
- Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul 07084, Korea; (H.-S.Y.); (H.-Y.K.)
- Correspondence: (K.-H.R.); (J.-W.P.); Tel.: +82-2-2653-3718 (K.-H.R.); +82-2-6986-6201 (J.-W.P.)
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48
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CD40L-expressing CD4+ T cells prime adipose-derived stromal cells to produce inflammatory chemokines. Cytotherapy 2022; 24:500-507. [DOI: 10.1016/j.jcyt.2022.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 12/21/2021] [Accepted: 01/20/2022] [Indexed: 11/18/2022]
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49
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Chen R, Hao Z, Wang Y, Zhu H, Hu Y, Chen T, Zhang P, Li J. Mesenchymal Stem Cell-Immune Cell Interaction and Related Modulations for Bone Tissue Engineering. Stem Cells Int 2022; 2022:7153584. [PMID: 35154331 PMCID: PMC8825274 DOI: 10.1155/2022/7153584] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 01/03/2022] [Indexed: 12/11/2022] Open
Abstract
Critical bone defects and related delayed union and nonunion are still worldwide problems to be solved. Bone tissue engineering is mainly aimed at achieving satisfactory bone reconstruction. Mesenchymal stem cells (MSCs) are a kind of pluripotent stem cells that can differentiate into bone cells and can be used as one of the key pillars of bone tissue engineering. In recent decades, immune responses play an important role in bone regeneration. Innate immune responses provide a suitable inflammatory microenvironment for bone regeneration and initiate bone regeneration in the early stage of fracture repair. Adaptive immune responses maintain bone regeneration and bone remodeling. MSCs and immune cells regulate each other. All kinds of immune cells and secreted cytokines can regulate the migration, proliferation, and osteogenic differentiation of MSCs, which have a strong immunomodulatory ability to these immune cells. This review mainly introduces the interaction between MSCs and immune cells on bone regeneration and its potential mechanism, and discusses the practical application in bone tissue engineering by modulating this kind of cell-to-cell crosstalk. Thus, an in-depth understanding of these principles of bone immunology can provide a new way for bone tissue engineering.
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Affiliation(s)
- Renxin Chen
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Zhuowen Hao
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Yi Wang
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Hongzhen Zhu
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Yingkun Hu
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Tianhong Chen
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Peng Zhang
- Department of Orthopedics, Suzhou Science and Technology Town Hospital, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou 215153, China
| | - Jingfeng Li
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
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Park Y, Kwok SK. Recent Advances in Cell Therapeutics for Systemic Autoimmune Diseases. Immune Netw 2022; 22:e10. [PMID: 35291648 PMCID: PMC8901702 DOI: 10.4110/in.2022.22.e10] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 01/26/2022] [Accepted: 01/27/2022] [Indexed: 12/03/2022] Open
Abstract
Systemic autoimmune diseases arise from loss of self-tolerance and immune homeostasis between effector and regulator functions. There are many therapeutic modalities for autoimmune diseases ranging from conventional disease-modifying anti-rheumatic drugs and immunosuppressants exerting nonspecific immune suppression to targeted agents including biologic agents and small molecule inhibitors aiming at specific cytokines and intracellular signal pathways. However, such current therapeutic strategies can rarely induce recovery of immune tolerance in autoimmune disease patients. To overcome limitations of conventional treatment modalities, novel approaches using specific cell populations with immune-regulatory properties have been attempted to attenuate autoimmunity. Recently progressed biotechnologies enable sufficient in vitro expansion and proper manipulation of such ‘tolerogenic’ cell populations to be considered for clinical application. We introduce 3 representative cell types with immunosuppressive features, including mesenchymal stromal cells, Tregs, and myeloid-derived suppressor cells. Their cellular definitions, characteristics, mechanisms of immune regulation, and recent data about preclinical and clinical studies in systemic autoimmune diseases are reviewed here. Challenges and limitations of each cell therapy are also addressed.
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Affiliation(s)
- Youngjae Park
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung-Ki Kwok
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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