Mesenchymal stem cells and T cells in the formation of Tertiary Lymphoid Structures in Lupus Nephritis

Abstract

Tertiary lymphoid structures (TLS) develop in the kidneys of lupus-prone mice and systemic lupus erythematosus (SLE) patients with lupus nephritis (LN). Here we investigated the presence of mesenchymal stem cells (MSCs) in the development of TLS in murine LN, as well as the role of human MSCs as lymphoid tissue organizer (LTo) cells on the activation of CD4+ T cells from three groups of donors including Healthy, SLE and LN patients. Mesenchymal stem like cells were detected within the pelvic wall and TLS in kidneys of lupus-prone mice. An increase in LTβ, CXCL13, CCL19, VCAM1 and ICAM1 gene expressions were detected during the development of murine LN. Human MSCs stimulated with the pro-inflammatory cytokines TNF-α and IL-1β significantly increased the expression of CCL19, VCAM1, ICAM1, TNF-α, and IL-1β. Stimulated MSCs induced proliferation of CD4+ T cells, but an inhibitory effect was observed when in co-culture with non-stimulated MSCs. A contact dependent increase in Th2 and Th17 subsets were observed for T cells from the Healthy group after co-culture with stimulated MSCs. Our data suggest that tissue-specific or/and migratory MSCs could have pivotal roles as LTo cells in accelerating early inflammatory processes and initiating the formation of kidney specific TLS in chronic inflammatory conditions.

Contribution of fibroblasts to tunnel formation and inflammation in hidradenitis suppurativa/ acne inversa

“…Fibroblasts are identified by their spindle‐shaped cellular morphology in combination with common mesenchymal markers such as vimentin and develop from multiple sources including resident tissue stromal cells, bone marrow–derived stromal cells, epithelial mesenchyme transition (EMT) and endothelial mesenchyme transition (endoMT) from epithelial and endothelial cells, respectively . The source of these stromal cells can be identified through examination of specific cell markers (such as PDGFR α, PDGFR β and podoplanin); however, no individual marker is known to be predictive of function. Transcriptomics and single‐cell RNA sequencing (scRNAseq) have recently been able to identify and characterize subpopulations of stromal cells and provide insights into their putative function in malignancy and inflammation.…”

“…Transcriptomics and single‐cell RNA sequencing (scRNAseq) have recently been able to identify and characterize subpopulations of stromal cells and provide insights into their putative function in malignancy and inflammation. Factors including cellular origin, spatial location, microenvironment and degree of differentiation all contribute to the functional phenotype (ie matrix remodelling, epithelial maintenance) of fibroblasts identified in these disorders . This results in a heterogeneous milieu of fibroblasts which are proposed to be differentially dysregulated in different forms of aberrant wound healing, fibrosis, hypertrophic scarring, malignancy and metastases .…”

“…Factors including cellular origin, spatial location, microenvironment and degree of differentiation all contribute to the functional phenotype (ie matrix remodelling, epithelial maintenance) of fibroblasts identified in these disorders . This results in a heterogeneous milieu of fibroblasts which are proposed to be differentially dysregulated in different forms of aberrant wound healing, fibrosis, hypertrophic scarring, malignancy and metastases . Common fibroblast subpopulations have been identified within chronic inflammatory conditions, chronic wound healing, malignancy and metastasis .…”

“…This results in a heterogeneous milieu of fibroblasts which are proposed to be differentially dysregulated in different forms of aberrant wound healing, fibrosis, hypertrophic scarring, malignancy and metastases . Common fibroblast subpopulations have been identified within chronic inflammatory conditions, chronic wound healing, malignancy and metastasis . This indicates common pathways may be at play, which are potential therapeutic targets in these various disorders (Figure ).…”

“…Fibroblast dysregulation has been implicated in impaired wound healing, inflammatory disorders such as pyoderma gangrenosum (associated with HS in the PASH and PAPASH syndromes), and in the development of tertiary lymphoid follicles in RA and IBD . Dysregulation is proposed to involve priming signals in the stromal environment during acute inflammation (mediated by granulocytes) to epigenetically modulate fibroblasts, leading to expression of markers including α‐SMA, S100A4 and FAP‐α .…”