Adipose‐derived stromal/stem cells successfully attenuate the fibrosis of scleroderma mouse models

Abstract

Aim Systemic sclerosis (SSc) is an autoimmune disease characterized by skin and lung fibrosis. Although SSc has a high mortality risk, an effective treatment for the disease has not been established yet. Mesenchymal stromal/stem cells (MSCs) are multipotential nonhematopoietic progenitor cells that have the ability to regulate immune responses. Adipose‐derived stromal/stem cells (ASCs), one of the types of MSCs, have the advantage of accessibility and potent immunomodulatory effects when compared with other MSCs, such as bone marrow‐derived MSCs. This study aimed to investigate the antifibrotic effect of ASCs in scleroderma mouse models, including bleomycin‐induced scleroderma and sclerodermatous chronic graft‐versus‐host disease (Scl‐cGVHD) models. Method ASCs were intravenously administered to a bleomycin‐induced scleroderma or Scl‐cGVHD model on day 0. We compared the skin and lung fibrosis of scleroderma model mice between the ASC‐treated group and control group. Results Administration of ASCs attenuated the skin and lung fibrosis of bleomycin‐induced scleroderma and Scl‐cGVHD model mice compared to that in the control mice. Immunohistochemical staining showed that ASCs suppressed the infiltration of CD4+, CD8+ T cells and macrophages into the dermis of bleomycin model mice compared to that in control mice. In addition, ASCs attenuated the messenger RNA expression of collagen and fibrogenic cytokines, such as interleukin (IL)‐6 and IL‐13, in the skin of bleomycin model mice. ASCs also reduced the frequency of fibrogenic cytokine‐producing CD4+ T cells and effector B cells in the spleen of bleomycin model mice. Conclusion ASCs could prove to be a potential therapeutic agent for use in patients with SSc.

Adipose-Derived Stem Cells Promote Intussusceptive Lymphangiogenesis by Restricting Dermal Fibrosis in Irradiated Tissue of Mice

“…Fibrosis is one of the major factors that inhibit lymphatic regeneration [4]. ADSC transplantation appears effective against fibrosis because ADSCs and their secreted factors activate dermal fibroblasts and suppress inflammatory cells [26,38]. ADSC transplantation should also be effective against lymphorrhea, promoting lymphatic regeneration and surrounding tissue normalization.…”

Perspective on Stem Cell Therapy in Organ Fibrosis: Animal Models and Human Studies

“…Other studies demonstrated that ASC administration was sufficient to attenuate BLM-induced scleroderma by suppressing the infiltration of CD4 + and CD8 + T cells and macrophages into the dermis, but it also reduced the frequency of CD4 + T cells and effector B cells in the spleens of SS mice [247]. Moreover, there was a decrease in mRNA expression of Col1a2 and profibrotic cytokines such as IL-6 and IL-13, suggesting an immunomodulatory and anti-inflammatory effect of ASCs in fibrotic skin [247].…”

“…Given that fibrotic skin diseases are complex, chronic, and heterogeneous and the evaluation of therapy is difficult, effective treatments have not been established so far. Nevertheless, among potential systemic antifibrotic therapies under investigation, those that employ MSCs have emerged as among the most promising [244][245][246][247][248].…”

Single-cell RNA Sequencing Reveals That Injected ADSCs Change the Macrophage Profile in a Murine Model of Pulmonary Fibrosis

“…ADSCs were found to stimulate the polarization of macrophages into the M2 phenotype by secreting IL-6 in the in ammatory environment of peritoneal brosis [20], or by activating the PI3K/STAT3-dependent pathway in cardiac brosis [21]. They were also reported to suppress the in ltration of macrophages and T cells into the injured side in a bleomycin-induced scleroderma model [22], prevent leucocyte in ltration and modulate the expression of IL-1b, TNF-a, IL-6 in a combined model of peritoneal brosis and chronic kidney disease [23]. Additionally, ADSCs increased the number of type II alveolar epithelial cells in a radiation-induced lung brosis model [24], and ameliorated radiation-induced brosis by secreting HGF to downregulating the expression of TGFβ, CTGF, IL-1, TNF and NF-κB, as well as recruiting BMSCs to the injured site [25].…”