Treatment with Mesenchymal Stromal Cells Overexpressing Fas-Ligand Ameliorates Acute Graft-versus-Host Disease in Mice

Vacaru, Andrei M.; Mazilu, Ana-Maria; Dumitrescu, M; Fenyo, Ioana Mădălina; Gafencu, Anca Violeta; Vacaru, Ana M.

doi:10.3390/ijms23010534

Cited by 4 publications

(3 citation statements)

References 33 publications

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“…A number of studies have also shown that MSCs express and secrete FasL [ 59 ]. It has been shown that FasL expression partly mediates the immunomodulatory properties of MSCs [ 60 , 61 , 62 ]. It is expected that the high expression of Fas makes these cells potentially susceptible to Fas-induced apoptosis [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

Resistance of Human Liver Mesenchymal Stem Cells to FAS-Induced Cell Death

Холоденко

Gisina

Manukyan

et al. 2022

CIMB

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Mesenchymal stem cells (MSCs) have a pronounced therapeutic potential in various pathological conditions. Though therapeutic effects of MSC transplantation have been studied for a long time, the underlying mechanisms are still not clear. It has been shown that transplanted MSCs are rapidly eliminated, presumably by apoptosis. As the mechanisms of MSC apoptosis are not fully understood, in the present work we analyzed MSC sensitivity to Fas-induced apoptosis using MSCs isolated from the biopsies of liver fibrosis patients (L-MSCs). The level of cell death was analyzed by flow cytometry in the propidium iodide test. The luminescent ATP assay was used to measure cellular ATP levels; and the mitochondrial membrane potential was assessed using the potential-dependent dye JC-1. We found that human L-MSCs were resistant to Fas-induced cell death over a wide range of FasL and anti-Fas mAb concentrations. At the same time, intrinsic death signal inducers CoCl2 and staurosporine caused apoptosis of L-MSCs in a dose-dependent manner. Despite the absence of Fas-induced cell death treatment of L-MSCs with low concentrations of FasL or anti-Fas mAb resulted in a cellular ATP level decrease, while high concentrations of the inducers caused a decline of the mitochondrial membrane potential. Pre-incubation of L-MSCs with the pro-inflammatory cytokine TNF-α did not promote L-MSC cell death. Our data indicate that human L-MSCs have increased resistance to receptor-mediated cell death even under inflammatory conditions.

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Section: Discussionmentioning

confidence: 99%

Resistance of Human Liver Mesenchymal Stem Cells to FAS-Induced Cell Death

Холоденко

Gisina

Manukyan

et al. 2022

CIMB

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“…The mechanism has been further elucidated in vitro through the transient knockdown of FasL, which revealed that activation of the Fas pathway induced MSC expression of MCP-1, promoting T lymphocyte recruitment and TGF-β expression in macrophages [74]. The transient effect of Fas-FasL pathway activation on T cells in a graft-versus-host disease (GvHD) model was improved by overexpressing FasL on MSCs in vitro and in vivo, suggesting an interesting therapeutic strategy for the treatment of GvHD [75,76].…”

Section: Mesenchymal Stromal Cells and Immunosuppressionmentioning

confidence: 99%

The critical role of apoptosis in mesenchymal stromal cell therapeutics and implications in homeostasis and normal tissue repair

et al. 2023

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Mesenchymal stromal cells (MSCs) have been extensively tested for the treatment of numerous clinical conditions and have demonstrated good safety but mixed efficacy. Although this outcome can be attributed in part to the heterogeneity of cell preparations, the lack of mechanistic understanding and tools to establish cell pharmacokinetics and pharmacodynamics, as well as the poorly defined criteria for patient stratification, have hampered the design of informative clinical trials. We and others have demonstrated that MSCs can rapidly undergo apoptosis after their infusion. Apoptotic MSCs are phagocytosed by monocytes/macrophages that are then reprogrammed to become anti-inflammatory cells. MSC apoptosis occurs when the cells are injected into patients who harbor activated cytotoxic T or NK cells. Therefore, the activation state of cytotoxic T or NK cells can be used as a biomarker to predict clinical responses to MSC treatment. Building on a large body of preexisting data, an alternative view on the mechanism of MSCs is that an inflammation-dependent MSC secretome is largely responsible for their immunomodulatory activity. We will discuss how these different mechanisms can coexist and are instructed by two different types of MSC “licensing”: one that is cell-contact dependent and the second that is mediated by inflammatory cytokines. The varied and complex mechanisms by which MSCs can orchestrate inflammatory responses and how this function is specifically driven by inflammation support a physiological role for tissue stroma in tissue homeostasis, and it acts as a sensor of damage and initiator of tissue repair by reprogramming the inflammatory environment.

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“…Regardless of the migration status, how MSCs prevent aGvHD in murine models remains unclear. Vacaru et al proposed a mode of action that involves the FasL pathway and showed that treatment with MSCs that overexpress FasL resulted in delayed GvHD onset and increased survival [ 119 ]. In another study, Wang Rui et al reported that MSCs derived from the umbilical cord express high levels of CXCL1, leading to the accumulation of myeloid-derived suppressor cells that control GvHD [ 120 ].…”

Section: Mscs In Mouse Models Of Gvhdmentioning

confidence: 99%

Current perspectives on mesenchymal stromal cell therapy for graft versus host disease

et al. 2023

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Graft versus host disease (GvHD) is the clinical condition in which bone marrow-derived mesenchymal stromal cells (MSCs) have been most frequently studied. In this review, we summarize the experience from clinical trials that have paved the way to translation. While MSC-based therapy has shown an exceptional safety profile, identifying potency assays and disease biomarkers that reliably predict the capacity of a specific MSC batch to alleviate GvHD has been difficult. As GvHD diagnosis and staging are based solely on clinical criteria, individual patients recruited in the same clinical trial may have vastly different underlying biology, obscuring trial outcomes and making it difficult to determine the benefit of MSCs in subgroups of patients. An accumulating body of evidence indicates the importance of considering not only the cell product but also patient-specific biomarkers and/or immune characteristics in determining MSC responsiveness. A mode of action where intravascular MSC destruction is followed by monocyte-efferocytosis-mediated skewing of the immune repertoire in a permissive inflammatory environment would both explain why cell engraftment is irrelevant for MSC efficacy and stress the importance of biologic differences between responding and nonresponding patients. We recommend a combined analysis of clinical outcomes and both biomarkers of disease activity and MSC potency assays to identify patients with GvHD who are likely to benefit from MSC therapy.

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Treatment with Mesenchymal Stromal Cells Overexpressing Fas-Ligand Ameliorates Acute Graft-versus-Host Disease in Mice

Cited by 4 publications

References 33 publications

Resistance of Human Liver Mesenchymal Stem Cells to FAS-Induced Cell Death

Resistance of Human Liver Mesenchymal Stem Cells to FAS-Induced Cell Death

The critical role of apoptosis in mesenchymal stromal cell therapeutics and implications in homeostasis and normal tissue repair

Current perspectives on mesenchymal stromal cell therapy for graft versus host disease

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