shun minatoguchi

Abstract Pancreatic stellate cells (PSCs) are stromal cells in the pancreas that play an important role in pancreatic pathology. In chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC), PSCs are known to get activated to form myofibroblasts or cancer‐associated fibroblasts (CAFs) that promote stromal fibroinflammatory reactions. However, previous studies on PSCs were mainly based on the findings obtained using ex vivo expanded PSCs, with few studies that addressed the significance of in situ tissue‐resident PSCs using animal models. Their contributions to fibrotic reactions in CP and PDAC are also lesser‐known. These limitations in our understanding of PSC biology have been attributed to the lack of specific molecular markers of PSCs. Herein, we established Meflin (Islr), a glycosylphosphatidylinositol‐anchored membrane protein, as a PSC‐specific marker in both mouse and human by using human pancreatic tissue samples and Meflin reporter mice. Meflin‐positive (Meflin⁺) cells contain lipid droplets and express the conventional PSC marker Desmin in normal mouse pancreas, with some cells also positive for Gli1, the marker of pancreatic tissue‐resident fibroblasts. Three‐dimensional analysis of the cleared pancreas of Meflin reporter mice showed that Meflin⁺ PSCs have long and thin cytoplasmic protrusions, and are localised on the abluminal side of vessels in the normal pancreas. Lineage tracing experiments revealed that Meflin⁺ PSCs constitute one of the origins of fibroblasts and CAFs in CP and PDAC, respectively. In these diseases, Meflin⁺ PSC‐derived fibroblasts showed a distinctive morphology and distribution from Meflin⁺ PSCs in the normal pancreas. Furthermore, we showed that the genetic depletion of Meflin⁺ PSCs accelerated fibrosis and attenuated epithelial regeneration and stromal R‐spondin 3 expression, thereby implying that Meflin⁺ PSCs and their lineage cells may support tissue recovery and Wnt/R‐spondin signalling after pancreatic injury and PDAC development. Together, these data indicate that Meflin may be a marker specific to tissue‐resident PSCs and useful for studying their biology in both health and disease. © 2023 The Pathological Society of Great Britain and Ireland.

Abstract Adipose-derived mesenchymal stem cells (ASCs) have shown therapeutic potentials against refractory diseases. However, the detailed therapeutic mechanisms remain unclear. Here, we report the therapeutic actions of human ASCs in nephritis, focusing on cellular dynamics and multi-organ networks. Intravenously-administered ASCs accumulated in spleen but not kidneys. Nevertheless, ASCs increased M2 macrophages and Tregs in kidneys and drove strong renoprotection. Splenectomy abolished these therapeutic effects. ASC-derived extracellular vesicles (EVs) were transferred to M2 macrophages, which entered the bloodstream from spleen. EVs induced the transcriptomic signatures of hyperpolarization and PGE2 stimulation in M2 macrophages and ameliorated glomerulonephritis. ASCs, ASC-derived EVs, and EV-transferred M2 macrophages enhanced Treg induction. These findings suggest that EV transfer from spleen-accumulated ASCs to M2 macrophages and subsequent modulation of renal immune-environment underlie the renoprotective effects of ASCs. Our results provide insights into the therapeutic actions of ASCs, focusing on EV-mediated modulation of macrophages and the spleen-kidney immune network.

Abstract Perivascular mesenchymal cells (PMCs), which include pericytes, give rise to myofibroblasts that contribute to chronic kidney disease progression. Several PMC markers have been identified; however, PMC heterogeneity and functions are not fully understood. Here, we describe a novel subset of renal PMCs that express Meflin, a glycosylphosphatidylinositol-anchored protein that was recently identified as a marker of fibroblasts essential for cardiac tissue repair. Tracing the lineage of Meflin⁺ PMCs, which are found in perivascular and periglomerular areas and exhibit renin-producing potential, showed that they detach from the vasculature and proliferate under disease conditions. Although the contribution of Meflin⁺ PMCs to conventional α-SMA⁺ myofibroblasts is low, they give rise to fibroblasts with heterogeneous α-SMA expression patterns. Genetic ablation of Meflin⁺ PMCs in a renal fibrosis mouse model revealed their essential role in collagen production. Consistent with this, human biopsy samples showed that progressive renal diseases exhibit high Meflin expression. Furthermore, Meflin overexpression in kidney fibroblasts promoted bone morphogenetic protein 7 signals and suppressed myofibroblastic differentiation, implicating the roles of Meflin in suppressing tissue fibrosis. These findings demonstrate that Meflin marks a PMC subset that is functionally distinct from classic pericytes and myofibroblasts, highlighting the importance of elucidating PMC heterogeneity.