A novel renal perivascular mesenchymal cell subset gives rise to fibroblasts distinct from classic myofibroblasts

Minatoguchi, Shun; Saito, Shoji; Furuhashi, Kazuhiro; Sawa, Yoshitaka; Okazaki, Mihoko; Shimamura, Yuko; Kaihan, Ahmad Baseer; Hashimoto, Yusaku; Yasuda, Yoshinari; Hara, Akitoshi; Mizutani, Yasuyuki; Ando, Ryosuke; Kato, Noritoshi; Ishimoto, Takuji; Tsuboi, Naotake; Esaki, Nobutoshi; Matsuyama, Makoto; Shiraki, Yukihiro; Kobayashi, Hiroki; Asai, Naoya; Enomoto, Atsushi; Maruyama, Shoichi

doi:10.1038/s41598-022-09331-5

Cited by 11 publications

(8 citation statements)

References 67 publications

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“…However, an important caveat is that in the present study pancreatic tissues 12 days post-PDL were assessed to avoid systemic toxicity of DTx administration in Meflin-ZDC mice, leaving the question open as to whether PSCs are primarily involved in regenerative and reparative or persistent fibrotic response after pancreatic injury. Interestingly, we and others previously found that Meflin is also expressed by fibroblasts in the heart, lung, kidney, and intestine, wherein it plays roles by providing protection against fibrosis and promoting tissue repair after tissue injuries [23,33,52,53]. Taken together with the present study, these studies will contribute to the understanding of the beneficial roles of fibroblasts in physiology and pathology.…”

Section: Discussionsupporting

confidence: 76%

“…It is noted that ZsGreen expression from the ZDC allele was so low in the pancreas that it did not affect the observation of mGFP fluorescence. Furthermore, we subjected the pancreata of Meflin-ZDC; LSL-mTmG mice to in vivo vascular staining by intravenous injection of an anti-CD31 antibody and isolectin B4, which binds to the endothelial cell surface [32,33], followed by tissue clearing [34] and three-dimensional (3D) observation by confocal microscopy (supplementary material, Figure S6B-D, Movies S1 and S2). The data showed that most Meflin + PSCs extend their long and thin cytoplasmic protrusions on the abluminal surface of the capillary lumen.…”

Section: Meflin Is a Psc Marker 65mentioning

confidence: 99%

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Meflin is a marker of pancreatic stellate cells involved in fibrosis and epithelial regeneration in the pancreas

Ando,

Shiraki,

Miyai

et al. 2023

The Journal of Pathology

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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.

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Section: Discussionsupporting

confidence: 76%

Section: Meflin Is a Psc Marker 65mentioning

confidence: 99%

Meflin is a marker of pancreatic stellate cells involved in fibrosis and epithelial regeneration in the pancreas

Ando,

Shiraki,

Miyai

et al. 2023

The Journal of Pathology

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“…The roles of rCAFs in rare types of cancer remain elusive [ 67 , 68 ]. Interestingly, Meflin + fibroblasts have been found in the stroma of non-tumor fibrotic diseases, such as cardiac fibrosis, idiopathic pulmonary fibrosis, and kidney fibrosis, where they seem to be essential for tissue repair, but also play a role in suppressing fibrosis, unlike α-SMA + myofibroblasts, which promote tissue fibrosis and stiffening [ 40 , 69 , 70 ]. These findings suggest common mechanisms and etiologies of cancer and fibrotic diseases.…”

Section: Discussionmentioning

confidence: 99%

Good and Bad Stroma in Pancreatic Cancer: Relevance of Functional States of Cancer-Associated Fibroblasts

Ando

Sakai

Iida

et al. 2022

Cancers

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A well-known feature of human pancreatic ductal adenocarcinoma (PDAC) is the extensive proliferation of cancer-associated fibroblasts (CAFs) and highly fibrotic stroma. Recent evidence, based mainly on single-cell analyses, has identified various subsets of CAFs in PDAC mouse models. However, we do not know how these CAF subsets are involved in the progression and drug resistance of human PDAC. Additionally, it remains unclear whether these diverse CAFs have distinct origins and are indicators of genuinely distinct CAF lineages or reflect different states of the same CAFs depending on the tumor microenvironment. Interestingly, recent preclinical studies have started to characterize the nature of cancer-restraining CAFs and have identified their markers Meflin and collagen type I alpha 1. These studies have led to the development of strategies to induce changes in CAF phenotypes using chemical reagents or recombinant viruses, and some of them have been tested in clinical studies. These strategies have the unique potential to convert the so-called bad stroma to good stroma and may also have therapeutic implications for non-cancer diseases such as fibrotic diseases. Together with recently developed sophisticated strategies that specifically target distinct CAF subsets via adoptive cell transfer therapy, vaccination, and antibody–drug conjugates, any future findings arising from these clinical efforts may expand our understanding of the significance of CAF diversity in human PDAC.

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“…However, no approved therapies for CKD are currently available. The final common pathway of CKD is fibrosis caused by the activation of interstitial fibroblasts to myofibroblasts, increased secretion and accumulation of the extracellular matrix, and loss or perturbation of tissue-specific epithelial cells and other cell lineages 3 – 5 .…”

Section: Introductionmentioning

confidence: 99%

Inducible deletion of microRNA activity in kidney mesenchymal cells exacerbates renal fibrosis

Sakuma,

Maruyama,

Aonuma

et al. 2024

Sci Rep

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MicroRNAs (miRNAs) are sequence-specific inhibitors of post-transcriptional gene expression. However, the physiological functions of these non-coding RNAs in renal interstitial mesenchymal cells remain unclear. To conclusively evaluate the role of miRNAs, we generated conditional knockout (cKO) mice with platelet-derived growth factor receptor-β (PDGFR-β)-specific inactivation of the key miRNA pathway gene Dicer. The cKO mice were subjected to unilateral ureteral ligation, and renal interstitial fibrosis was quantitatively evaluated using real-time polymerase chain reaction and immunofluorescence staining. Compared with control mice, cKO mice had exacerbated interstitial fibrosis exhibited by immunofluorescence staining and mRNA expression of PDGFR-β. A microarray analysis showed decreased expressions of miR-9-5p, miR-344g-3p, and miR-7074-3p in cKO mice compared with those in control mice, suggesting an association with the increased expression of PDGFR-β. An analysis of the signaling pathways showed that the major transcriptional changes in cKO mice were related to smooth muscle cell differentiation, regulation of DNA metabolic processes and the actin cytoskeleton, positive regulation of fibroblast proliferation and Ras protein signal transduction, and focal adhesion-PI3K/Akt/mTOR signaling pathways. Depletion of Dicer in mesenchymal cells may downregulate the signaling pathway related to miR-9-5p, miR-344g-3p, and miR-7074-3p, which can lead to the progression of chronic kidney disease. These findings highlight the possibility for future diagnostic or therapeutic developments for renal fibrosis using miR-9-5p, miR-344g-3p, and miR-7074-3p.

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A novel renal perivascular mesenchymal cell subset gives rise to fibroblasts distinct from classic myofibroblasts

Cited by 11 publications

References 67 publications

Meflin is a marker of pancreatic stellate cells involved in fibrosis and epithelial regeneration in the pancreas

Meflin is a marker of pancreatic stellate cells involved in fibrosis and epithelial regeneration in the pancreas

Good and Bad Stroma in Pancreatic Cancer: Relevance of Functional States of Cancer-Associated Fibroblasts

Inducible deletion of microRNA activity in kidney mesenchymal cells exacerbates renal fibrosis

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