Pathogenic Activation of Mesenchymal Stem Cells Is Induced by the Disease Microenvironment in Systemic Sclerosis

Abstract

Objective In systemic sclerosis (SSc) a persistent tissue repair process leads to progressive fibrosis of the skin and internal organs. The role of mesenchymal stem cells (MSCs), which characteristically initiate and regulate tissue repair, has not been fully evaluated. We sought to investigate whether dividing metakaryotic MSCs are present in SSc skin, and test whether exposure to the disease microenvironment activates MSCs leading to transdifferentation. MethodsSkin biopsy material from recent onset diffuse SSc patients was examined by collagenase spread of 1mm thick surface-parallel sections, in order to identify metakarytoic dividing stem cells in each tissue plane. Adipose-derived MSCs from healthy controls were treated with dermal blister fluid from diffuse SSc patients, and profiled by next generation sequencing, or evaluated for phenotypic changes relevant to SSc. Differential responses of dermal fibroblasts were studied in parallel. Results MSC-like cells undergoing active metakaryotic division were identified in SSc but not control sections, most prominent in the deep dermis and adjacent to damaged microvessels, in both involved and clinically uninvolved skin. Furthermore, exposure to SSc blister fluid caused selective MSC activation, inducing a myofibroblast signature, whilst reducing signatures of vascular repair and adipogenesis and enhancing migration and contractility. Microenvironment factors implicated in inducing transdifferentiation include the pro-fibrotic growth factor TGFβ, presence of lactate and mechanosensing, whereas the microenvironment Th2 cytokine IL-31, enhanced osteogenic commitment (calcinosis). Conclusion Dividing MSC-like cells are present in the SSc disease microenvironment where multiple factors, likely acting in concert, promote transdifferentiation, leading to a complex and resistant disease state.

Pathophysiology of systemic sclerosis (scleroderma)

“…In vitro TGFβ stimulation of mouse adipocytes causes adipocyte‐myofibroblast transition (AMT), a loss of adipogenesis, and an upregulation of profibrotic genes in the cells 81 . Subcutaneous adipose mesenchymal stem cells 82 and mature adipocytes are both involved in the transdifferentiation into fibroblast‐like cells 83 . It has also been shown that the adipocytes from fibrotic locations in SSc are phenotypically different from normal adipocytes 83 .…”

One year in review 2021: systemic sclerosis

“…In those skin samples, MSC-like cells undergoing megakaryocytic division were identified in both involved and uninvolved skin, and exposure to dermal blister fluid caused MSC activation, inducing a myofibroblast phenotype. This suggests that the disease microenvironment may influence the differentiation of MSCs toward a profibrotic phenotype, being responsible for the establishment of the disease (16). It is also likely that the microenvironment is involved in the activation of SSc macrophages toward a profibrotic pattern with overexpression of CCL2, IL-6 and TGF-β.…”

“…• ECM and soluble factors in SSc microenvironment are gaining growing importance in SSc profibrotic activation (13,16,17,20).…”

Strategies for improving adipose-derived stem cells for tissue regeneration

“…First, as to the source of stem cells, autologous ADSCs are always a favorable choice. However, the inherent disease context of patients, such as systemic sclerosis [ 159 ], atherosclerosis [ 160 ], diabetes [ 161 ], obesity [ 162 , 163 ], aging [ 164 ] etc., might impair the reserve, secretory profiles and functional properties of ADSCs. Although serious adverse events on usage of allogenic ADSCs have rarely been reported so far, suggesting that cells from allogenic source are well tolerated [ 165–167 ], more evidence is needed to justify the clinical use of allogenic ADSCs.…”