Mesenchymal stem (stromal) cells (MSCs) are multipotent cells with the ability to differentiate into several cell types, thus serving as a cell reservoir for regenerative medicine. Much of the ...current interest in therapeutic application of MSCs to various disease settings can be linked to their immunosuppressive and anti-inflammatory properties. One of the key mechanisms of MSC anti-inflammatory effects is the secretion of soluble factors with paracrine actions. Recently it has emerged that the paracrine functions of MSCs could, at least in part, be mediated by extracellular vesicles (EVs). EVs are predominantly released from the endosomal compartment and contain a cargo that includes miRNA, mRNA, and proteins from their cells of origin. Recent animal model-based studies suggest that EVs have significant potential as a novel alternative to whole cell therapies. Compared to their parent cells, EVs may have a superior safety profile and can be safely stored without losing function. In this article, we review current knowledge related to the potential use of MSC-derived EVs in various diseases and discuss the promising future for EVs as an alternative, cell-free therapy.
Impaired healing of cutaneous wounds and ulcers continues to have a major impact on the quality of life of millions of people. In recent years, the capacity for stem and progenitor cells to promote ...wound repair has been investigated with evidence that secreted factors are responsible for the observed therapeutic benefits. This review addresses current evidence in support of stem/progenitor cell-derived extracellular vesicles (EVs) as a regenerative therapy for acceleration of wound healing. Encouraging results for local or systemic administration of EVs have been reported in a range of clinically-relevant animal models of cutaneous wounds. Furthermore, a number of plausible mechanisms involving EV-mediated transfer of proteins and RNAs that trigger pro-repair pathways in target cells have been demonstrated experimentally. However, for successful clinical translation in the coming years, further emphasis on standardized experimental protocols, detailed methodological reporting and clear definition of EV-based therapeutic products will be required.
Display omitted
Mesenchymal stromal cells (MSC) have been used to treat a broad range of disease indications such as acute and chronic inflammatory disorders, autoimmune diseases, and transplant rejection due to ...their potent immunosuppressive/anti-inflammatory properties. The breadth of their usage is due in no small part to the vast quantity of published studies showing their ability to modulate multiple immune cell types of both the innate and adaptive immune response. While patient-derived (autologous) MSC may be the safer choice in terms of avoiding unwanted immune responses, factors including donor comorbidities may preclude these cells from use. In these situations, allogeneic MSC derived from genetically unrelated individuals must be used. While allogeneic MSC were initially believed to be immune-privileged, substantial evidence now exists to prove otherwise with multiple studies documenting specific cellular and humoral immune responses against donor antigens following administration of these cells. In this article, we will review recent published studies using non-manipulated, inflammatory molecule-activated (licensed) and differentiated allogeneic MSC, as well as MSC extracellular vesicles focusing on the immune responses to these cells and whether or not such responses have an impact on allogeneic MSC-mediated safety and efficacy.
Mesenchymal stem (stromal) cells (MSCs) have potent anti‐inflammatory/immunosuppressive properties which underlie much of their therapeutic potential. This fact has led to the widely accepted belief ...that MSCs from genetically unrelated individuals (allogeneic (allo)‐MSCs) can be used therapeutically with equal efficacy to autologous MSCs and without triggering the donor‐specific immune responses that are typically associated with allo‐transplants. In this article, we critically review available experimental data to determine whether good in vivo evidence exists in support of the ‘immune privileged’ status of allo‐MSCs. We also examine published studies regarding the immunogenicity of allo‐MSCs following activation (‘licensing’) by inflammatory stimuli or following differentiation. Among the identified studies which have addressed in vivo immunogenicity of allo‐MSCs, there was substantial variability as regards experimental species, disease model, route of MSC administration, cell dose and stringency of the immunological assays employed. Nonetheless, the majority of these studies has documented specific cellular (T‐cell) and humoral (B‐cell/antibody) immune responses against donor antigens following administration of non‐manipulated, interferon‐γ‐activated and differentiated allo‐MSCs. The consequences of such anti‐donor immune responses were also variable and ranged from reduced in vivo survival of allo‐MSCs with accelerated rejection of subsequent allogeneic transplants to apparent promotion of donor‐specific tolerance. On the basis of these findings and on existing knowledge of allo‐antigen recognition from the field of transplant immunology, we propose that the concept of the immune privileged nature of allo‐MSCs should be reconsidered and that the range and clinical implications of anti‐donor immune responses elicited by allo‐MSCs be more precisely studied in human and animal recipients.
The January 2013 issue contains a Special Feature Focussing on the interface between mesenchymal stromal cells and the immune system. Mesenchymal stromal cells (MSCs) are known to play a fundamental role in supporting hematopoiesis and are multipotent. This knowledge has led to significant interest to determine the potential of using MSCs both to enhance hematopoietic recovery following bone marrow transplantation and also for regenerative medical purposes. Further studies showed that MSCs also had immunosuppressive activity on both the adaptive and natural immune system, thereby endorsing them as the perfect cell source for tissue repair. The Special Feature contains review articles covering topics that largely focus on the interactions of MSCs with cells of the immune system. Further background information on this important topic is available through the accompanying web focus which links to related articles from across Nature Publishing Group.
Although there have been many advances in recent years for the treatment of colorectal cancer (CRC), it still remains the third most common cause of cancer-related deaths worldwide. Many patients ...with late stage CRC display resistance to multiple different therapeutics. An important aspect in developing effective therapeutics for CRC patients is understanding the interactions that take place in the tumor microenvironment (TME), as it has been shown to contribute to drug resistance in vivo. Much research over the past 100 years has focused on 2D monolayer cultures or in vivo studies, however, the efficacy in translating these to the clinic is very low. More recent studies are turning towards developing an effective 3D model of CRC that is clinically relevant, that can recapitulate the TME in vitro and bridge the gap between 2D cultures and in vivo studies, with the aim of reducing the use of animal models in the future. This review summarises the advantages and limitations of different 3D CRC models. It emphasizes how different 3D models may be optimised to study cellular and extracellular interactions that take place in the TME of CRC in an effort to allow the development of more translatable effective treatment options for patients.
ABSTRACT
Mesenchymal stromal cells (MSCs) have shown promise as a therapy for immune‐mediated disorders, including transplant rejection. Our group previously demonstrated the efficacy of ...pretransplant, systemic administration of allogeneic but not syngeneic MSCs in a rat cornea transplant model. The aim of this study was to enhance the immunomodulatory capacity of syngeneic MSCs. In vitro, MSCs licensed with TNF‐α/IL‐1β (MSCsTNF‐α/IL‐1β) suppress syngeneic lymphocyte proliferation via NO production. In vivo, when administered post‐transplantation, non‐licensed syngeneic MSCs improved graft survival from 0 to 50% and MSCsTNF‐α/IL‐1β, in an NO‐dependent manner, improved survival to 70%. Improved survival was associated with increased CD4+CD25+ forkhead box P3+ regulatory T (Treg) cells and decreased proinflammatory cytokine expression in the draining lymph node. MSCsTNF‐α/IL‐1β demonstrated a more potent immunomodulatory capacity compared with nonlicensed MSCs, promoting an immune‐regulatory CD11b+B220+ monocyte/macrophage population and significantly expanding Treg cells in the lungs and spleen. Ex vivo, we observed that lung‐derived myeloid cells act as intermediaries of MSC immunomodulatory function. MSC‐conditioned myeloid cells suppressed stimulated lymphocyte proliferation and promoted expansion of Treg cells from naive lymphocytes. This work illustrates how syngeneic MSC therapy can be enhanced by licensing and optimization of timing strategies and further highlights the important role of myeloid cells in mediating MSC immunomodulatory capacity.—Murphy, N., Treacy, O., Lynch, K., Morcos, M., Lohan, P., Howard, L., Fahy, G., Griffin, M. D., Ryan, A. E., Ritter, T. TNF‐α/IL‐1β—licensed mesenchymal stromal cells promote corneal allograft survival via myeloid cell—mediated induction of Foxp3+ regulatory T cells in the lung. FASEB J. 33, 9404–9421 (2019). www.fasebj.org
Proinflammatory signaling pathways are commonly up-regulated in breast cancer. In estrogen receptor-negative (ER⁻) and triple-negative breast cancer (TNBC), nitric oxide synthase-2 (NOS2) and ...cyclooxygenase-2 (COX2) have been described as independent predictors of disease outcome. We further explore these findings by investigating the impact of their coexpression on breast cancer survival. Elevated coexpression of NOS2/COX2 proteins is a strong predictor of poor survival among ER⁻ patients (hazard ratio: 21). Furthermore, we found that the key products of NOS2 and COX2, NO and prostaglandin E2 (PGE2), respectively, promote feed-forward NOS2/COX2 crosstalk in both MDA-MB-468 (basal-like) and MDA-MB-231 (mesenchymal-like) TNBC cell lines in which NO induced COX2 and PGE2 induced NOS2 proteins. COX2 induction by NO involved TRAF2 activation that occurred in a TNFα-dependent manner in MDA-MB-468 cells. In contrast, NO-mediated TRAF2 activation in the more aggressive MDA-MB-231 cells was TNFα independent but involved the endoplasmic reticulum stress response. Inhibition of NOS2 and COX2 using amino-guanidine and aspirin/indomethacin yielded an additive reduction in the growth of MDA-MB-231 tumor xenografts. These findings support a role of NOS2/COX2 crosstalk during disease progression of aggressive cancer phenotypes and offer insight into therapeutic applications for better survival of patients with ER⁻ and TNBC disease.
Mesenchymal stromal cells (MSCs) are a promising therapeutic option for multiple immune diseases/disorders; however, efficacy of MSC treatments can vary significantly. We present a novel licensing ...strategy to improve the immunosuppressive capacity of MSCs. Licensing murine MSCs with transforming growth factor-β1 (TGF-β MSCs) significantly improved their ability to modulate both the phenotype and secretome of inflammatory bone marrow-derived macrophages and significantly increased the numbers of regulatory T lymphocytes following co-culture assays. These TGF-β MSC-expanded regulatory T lymphocytes also expressed significantly higher levels of PD-L1 and CD73, indicating enhanced suppressive potential. Detailed analysis of T lymphocyte co-cultures revealed modulation of secreted factors, most notably elevated prostaglandin E2 (PGE2). Furthermore, TGF-β MSCs could significantly prolong rejection-free survival (69.2% acceptance rate compared to 21.4% for unlicensed MSC-treated recipients) in a murine corneal allograft model. Mechanistic studies revealed that (1) therapeutic efficacy of TGF-β MSCs is Smad2/3-dependent, (2) the enhanced immunosuppressive capacity of TGF-β MSCs is contact-dependent, and (3) enhanced secretion of PGE2 (via prostaglandin EP4 E-type prostanoid 4 receptor) by TGF-β MSCs is the predominant mediator of Treg expansion and T cell activation and is associated with corneal allograft survival. Collectively, we provide compelling evidence for the use of TGF-β1 licensing as an unconventional strategy for enhancing MSC immunosuppressive capacity.
Display omitted
Ritter and colleagues evaluated the therapeutic efficacy of transforming growth factor (TGF)-β1-licensed mesenchymal stromal cells (MSCs) in an allogeneic murine corneal transplant model. TGF-β1 MSCs demonstrated potent immunosuppressive ability in vitro and significantly prolonged corneal allograft survival associated with prostaglandin E2 (PGE2)-mediated peripheral regulatory T cell expansion.
Immune checkpoint inhibitors (ICIs) have improved overall survival for cancer patients, however, optimal duration of ICI therapy has yet to be defined. Given ICIs were first used to treat patients ...with metastatic melanoma, a condition that at the time was incurable, little attention was initially paid to how much therapy would be needed for a durable response. As the early immunotherapy trials have matured past 10 years, a significant per cent of patients have demonstrated durable responses; it is now time to determine whether patients have been overtreated, and if durable remissions can still be achieved with less therapy, limiting the physical and financial toxicity associated with years of treatment. Well-designed trials are needed to identify optimal duration of therapy, and to define biomarkers to predict who would benefit from shorter courses of immunotherapy. Here, we outline key questions related to health, financial and societal toxicities of over treating with ICI and present four unique clinical trials aimed at exposing criteria for early cessation of ICI. Taken together, there is a serious liability to overtreating patients with ICI and future work is warranted to determine when it is safe to stop ICI.
High-risk cornea transplant recipients represent a patient population with significant un-met medical need for more effective therapies to prevent immunological graft rejection due to heightened ...anti-donor immune response. In this study, a rat model of pre-existing anti-donor immunity was developed in which corneal allografts were rejected earlier than in non-pre-sensitized recipients. In this model, third-party (non-donor, non-recipient strain) allogeneic mesenchymal stromal cells (allo-MSC) were administered intravenously 7 and 1 days prior to transplantation. Rejection-free graft survival to 30 days post-transplant improved from 0 to 63.6% in MSC-treated compared to vehicle-treated control animals (
= < 0.0001). Pre-sensitized animals that received third-party allo-MSC prior to transplantation had significantly higher proportions of CD45
CD11b
B220
monocytes in the lungs 24 h after the second MSC injection and significantly higher proportions of CD4
FoxP3
regulatory T cells in the graft-draining lymph nodes at the average day of rejection of control animals. In
experiments, third-party allo-MSC polarized primary lung-derived CD11b/c
myeloid cells to a more anti-inflammatory phenotype, as determined by cytokine profile and conferred them with the capacity to suppress T cell activation via prostaglandin E
and TGFβ1. In experiments designed to further validate the clinical potential of the protocol, thawed cryopreserved, third-party allo-MSC were shown to be similarly potent at prolonging rejection-free corneal allograft survival as their freshly-cultured counterparts in the pre-sensitized high-risk model. Furthermore, thawed cryopreserved third-party allo-MSC could be co-administered with mycophenolate mofetil without adversely affecting their immunomodulatory function. In conclusion, a clinically-relevant protocol consisting of two intravenous infusions of third-party allo-MSC during the week prior to transplantation, exerts a potent anti-rejection effect in a pre-sensitized rat model of high-risk corneal allo-transplantation. This immune regulatory effect is likely to be mediated in the immediate post-transplant period through the promotion, by allo-MSC, of alternatively-activated macrophages in the lung and, later, by enhanced regulatory T-cell numbers.
PDF
