Mesenchymal Stem Cells (MSCs) Attenuate Cutaneous Sclerodermatous Graft-Versus-Host Disease (Scl-GVHD) through Inhibition of Immune Cell Infiltration in a Mouse Model

Lim, Jung Sub; Ryu, Da-Bin; Lee, Sung‐Eun; Park, Gyeongsin; Min, Chang‐Ki

doi:10.1016/j.jid.2017.02.986

Cited by 38 publications

(31 citation statements)

References 47 publications

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“…Moreover, they demonstrated that BM-MSCs recruited T-cells for FASL-mediated apoptosis through the secretion of Monocyte Chemotactic Protein 1 (MCP-1) ( 47 ). Another study also demonstrates that allogeneic MSCs could attenuate a mice model of cutaneous sclerodermatous GVHD by selectively blocking immune cell migration and down-regulating chemokines and chemokine receptors ( 48 ).…”

Section: Rational Of Msc-based Therapy Of Sscmentioning

confidence: 99%

Mesenchymal Stromal Cells Based Therapy in Systemic Sclerosis: Rational and Challenges

Peltzer¹,

Aletti

Frescaline

et al. 2018

Front. Immunol.

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Systemic Sclerosis (SSc) is a rare chronic disease, related to autoimmune connective tissue diseases such as Systemic Lupus Erythematosus and Sjögren's Syndrome. Although its clinical heterogeneity, main features of the disease are: extensive tissue fibrosis with increase matrix deposition in skin and internal organ, microvascular alterations and activation of the immune system with autoantibodies against various cellular antigens. In the diffuse cutaneous scleroderma subtype, the disease is rapidly progressive with a poor prognosis, leading to failure of almost any internal organ, especially lung which is the leading cause of death. Primary trigger is unknown but may involve an immune process against mesenchymal cells in a genetically receptive host. Pathophysiology reveals a pivotal role of fibrosis and inflammation alterations implicating different cell subtypes, cytokines and growth factors, autoantibodies and reactive oxygen species. Despite improvement, the overall survival of SSc patients is still lower than that of other inflammatory diseases. Recommended drugs are agents capable of modulating fibrotic and inflammatory pathways. Cellular therapy has recently emerged as a credible option. Besides autologous hematopoietic stem cell transplantation which demonstrated remarkable improvement, mesenchymal stromal cells (MSCs) represent promising therapeutic candidates. Indeed, these cells possess anti-inflammatory, antiproliferative, antifibrotic, and immunomodulary properties especially by secreting a large panel of bioactive molecules, addressing the most important key points of the SSc. In addition, these cells are very sensitive to their environment and are able to modulate their activity according to the pathophysiological context in which they are located. Autologous or allogeneic MSCs from various sources have been tested in many trials in different auto-immune diseases such as multiple sclerosis, Crohn's disease or systemic lupus erythematosus. They are characterized by a broad availability and no or low acute toxicity. However, few randomized prospective clinical trials were published and their production under ATMP regulatory procedures is complex and time-consuming. Many aspects have still to be addressed to ascertain their potential as well as the potential of their derived products in the management of SSc, probably in association with other therapies.

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Section: Rational Of Msc-based Therapy Of Sscmentioning

confidence: 99%

Mesenchymal Stromal Cells Based Therapy in Systemic Sclerosis: Rational and Challenges

Peltzer¹,

Aletti

Frescaline

et al. 2018

Front. Immunol.

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“…In this murine Scl-GVHD model (34), infiltration of mononuclear cells (predominantly CD4 T cells and CD11b monocyte/macrophages) into target organs starts 14 days after allo-HSCT (8,11,35). After injection of hMSCs, the infiltration of mononuclear cells was profoundly reduced into the skin, whereas in the lungs, an increase in infiltrating CD4 T cells followed the early accumulation of CD11b cells.…”

Section: Discussionmentioning

confidence: 99%

“…The entry of leukocytes into lymphoid and nonlymphoid tissues is controlled by sequential engagement of inflammatory cytokines and/or chemokines (36,37). It has been previously shown that mMSCs attenuate cutaneous Scl-GVHD by selectively blocking immune cell migration and down-regulating chemokines and chemokine receptors (11). We wondered whether chemokine expression pattern was a factor determining the preferential organ involvement after early injection of hMSCs, which led us to analyze chemokine receptors involved in lung diseases (38).…”

Section: Discussionmentioning

confidence: 99%

“…Mesenchymal stem cells (MSCs) are stromal cells that normally reside within the adult bone marrow and can differentiate into many adult cell types, such as osteocytes, chondrocytes and adipocytes (10). We previously reported that allogeneic murine MSCs (mMSCs) attenuate cutaneous Scl-GVHD by selectively blocking immune cell migration and downregulating chemokines and chemokine receptors in the murine Scl-GVHD model (11). To improve clinical applicability, we chose to study human MSCs (hMSCs), given the multiple differences in immunomodulatory effects between the two MSCs.…”

Section: Introductionmentioning

confidence: 99%

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CCL1 blockade alleviates human mesenchymal stem cell (hMSC)-induced pulmonary fibrosis in a murine sclerodermatous graft-versus-host disease (Scl-GVHD) model

Lim

Ryu

Kim

et al. 2020

Preprint

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Background Human chronic graft-versus-host disease (CGVHD) shares clinical characteristics with a murine sclerodermatous GVHD (Scl-GVHD, B10.D2 → BALB/c) model that is characterized by skin and lung fibrosis. In this study, bone marrow- or adipose tissue-derived human mesenchymal stem cells (hMSCs) were injected into the Scl-GVHD mice to address their therapeutic effect on CGVHD. Methods Lethally irradiated BALB/c mice were transplanted with B10.D2 T cell depleted bone marrow with or without spleen cells to generate Scl GVHD. hMSCs were intravenously treated on days 3, 5 and 7 post-transplantation. And the control antibody or CCL1 blocking antibody was subcutaneously injected into the same schedule as hMSCs. At 14 days after transplantation, the recipient mice sacrificed and their skin and lung analyzed. Results After early injection of hMSCs after transplantation, the clinical and pathological severity of Scl-GVHD in the skin was significantly attenuated, whereas the pathological score was exacerbated in the lungs. hMSCs migrated into the lungs but not into the skin. CD11b monocyte/macrophages and CD4 T cells were markedly decreased in skin tissues, whereas there was an early recruitment of CD11b cells, and subsequently increased infiltration of CD4 T cells, in the lungs. Importantly, hMSCs persistently up-regulated the expression of CCL1 in the lungs but not in the skin. Concurrent treatment of hMSCs with a CCL1-blocking antibody alleviated the severity of the lung histopathology score and fibrosis with preservation of the cutaneous protective effect against CGVHD. Infiltration of CD3 T cells and CD68 macrophages and up-regulation of chemokines were also decreased in lung tissues, along with recruitment of eosinophils and tissue IgE expression. In the skin, chemokine expression was further reduced after CCL1 blockade. Conclusions These data demonstrate that despite a protective effect against Scl-GVHD in the skin, administration of hMSCs exacerbated lung fibrosis associated with eosinophilia and airway inflammation through persistent CCL1 up-regulation. CCL1 blockade offers a potential treatment of pulmonary complications induced after treatment with hMSCs.

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“…The clinical characteristics of human chronic graft-versus-host disease (cGVHD) are similar to that of murine sclerodermatous GVHD model such as skin hyperkeratosis and pulmonary fibrosis. Lim et al indicated that MSCs were correlated with the remission of cutaneous sclerodermatous GVHD, whose potential mechanism might be down-regulating the migration of immune cells and eliminating the secretion of chemokines [96]. Research on MSCs applied in chronic anti-graft host disease (cGVHD) started rather late and is far from enough, which requires further research.…”

Section: Application In Chronic Graft-versus-host Disease (Cgvhd)mentioning

confidence: 99%

Mesenchymal stem cells: a promising way in therapies of graft-versus-host disease

et al. 2020

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It is well acknowledged that allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for numerous malignant blood diseases, which has also been applied to autoimmune diseases for more than a decade. Whereas graft-versus-host disease (GVHD) occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT) as a common serious complication, seriously affecting the efficacy of transplantation. Mesenchymal stem cells (MSCs) derived from a wealth of sources can easily isolate and expand with low immunogenicity. MSCs also have paracrine and immune regulatory functions, leading to a broad application prospect in treatment and tissue engineering. This review focuses on immunoregulatory function of MSCs, factors affecting mesenchymal stem cells to exert immunosuppressive effects, clinical application of MSCs in GVHD and researches on MSC-derived extracellular vesicles (EVs). The latest research progress on MSC in related fields is reviewed as well. The relevant literature from PubMed databases is reviewed in this article.

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Mesenchymal Stem Cells (MSCs) Attenuate Cutaneous Sclerodermatous Graft-Versus-Host Disease (Scl-GVHD) through Inhibition of Immune Cell Infiltration in a Mouse Model

Cited by 38 publications

References 47 publications

Mesenchymal Stromal Cells Based Therapy in Systemic Sclerosis: Rational and Challenges

Mesenchymal Stromal Cells Based Therapy in Systemic Sclerosis: Rational and Challenges

CCL1 blockade alleviates human mesenchymal stem cell (hMSC)-induced pulmonary fibrosis in a murine sclerodermatous graft-versus-host disease (Scl-GVHD) model

Mesenchymal stem cells: a promising way in therapies of graft-versus-host disease

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