Mesenchymal stem cells alleviate systemic sclerosis by inhibiting the recruitment of pathogenic macrophages

Abstract

Systemic sclerosis (SSc) is a recalcitrant autoimmune disease for which there is no cure. Mesenchymal stem cell (MSC)-based treatment has emerged as a promising therapeutic option for several autoimmune diseases. Previously, we found that the immunoregulatory potential of MSCs can be greatly enhanced by IFN-γ and TNF-α. Here, we found that IFN-γ- and TNF-α-pretreated MSCs significantly alleviated skin fibrosis in a bleomycin (BLM)-induced SSc model. Macrophages were found to be the predominant profibrotic immune cell population in the pathogenesis of SSc. The accumulation of macrophages was significantly decreased by MSC treatment. Importantly, MSCs primarily reduced the population of maturing macrophages with high CCR2 expression by inhibiting the generation of CCL2 from fibroblasts and macrophages. This finding may help to improve MSC-based clinical treatments for SSc patients.

Emerging cellular and immunotherapies for systemic sclerosis: from mesenchymal stromal cells to CAR-T cells and vaccine-based approaches

“…Injection of xenogenic bone marrow derived MSC (BM-MSC) and adipocyte-derived MSC (ASC) also decreased skin and lung fibrosis in this model [12]. Xenogenic umbilical cord derived human MSC or mouse ASC injection similarly prevented the onset of skin fibrosis in the subcutaneous bleomycin-induced disease model [13 ▪▪ ,14]. MSC especially prevented the recruitment of CCR2 high-CD64+Ly6C+maturing macrophages by suppressing the chemoattractant CCL-2, demonstrating the importance of MSC-macrophage interactions in the therapeutic effects of this cellular therapy.…”

Plasticity and crosstalk of mesenchymal stem cells and macrophages in immunomodulation in sepsis

“…In this environment, high levels of proinflammatory factors activate the immunosuppressive switch in MSCs, thereby mitigating excessive inflammatory responses ( Figure 4B ). Several studies also emphasized the crucial role of IFN-γ in inducing the anti-inflammatory effects of MSCs ( 87 , 88 , 146 ). Furthermore, IFN-γ produced by activated T cells can directly upregulate PD-L1 expression on MSCs, leading to the inhibition of T-cell proliferation in coculture systems ( 147 ), which suggests that the anti-inflammatory effects of MSCs are mediated not only through paracrine signalling but also through direct cell-to-cell contact.…”