Temporal control of PDGFRα regulates the fibroblast-to-myofibroblast transition in wound healing

Yao, Longbiao; Rathnakar, Bharath; Kwon, Hae Ryong; Sakashita, Hiromi; Kim, Jang Hwan; Rackley, Alex; Tomasek, James J.; Berry, William L.; Olson, Lorin E.

doi:10.1016/j.celrep.2022.111192

Cited by 35 publications

(31 citation statements)

References 77 publications

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“…Given the extensive fibrotic response, the very small numbers of Gli1 + cells, and the inconsistent transcriptional responses of these cells, it’s unlikely that the Gli1 + cells are significant contributors to this fibrotic response. We also examined cells expressing PDGFRα and/or β, as these cells have previously been identified as fibrogenic (Ajay et al, 2022; Buhl et al, 2020; Kikuchi et al, 2020; Kocabayoglu et al, 2015; R. Li et al, 2018; Santini et al, 2020; Yao et al, 2022). In wild type glands, there was an increase in PDGFRα + stromal cells after injury.…”

Section: Discussionmentioning

confidence: 99%

Identifying Fibrogenic Cells Following Salivary Gland Obstructive Injury

Altrieth

O’Keefe

Gellatly

et al. 2023

Preprint

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Fibrosis results from excess extracellular matrix accumulation, which alters normal tissue architecture and impedes function. In the salivary gland, fibrosis can be induced by irradiation treatment for cancer therapy, Sjögrens Disease, and other causes; however, it is unclear which stromal cells and signals participate in injury responses and disease progression. As hedgehog signaling has been implicated in fibrosis of the salivary gland and other organs, we examined contributions of the hedgehog effector, Gli1, to fibrotic responses in salivary glands. To experimentally induce a fibrotic response in female murine submandibular salivary glands, we performed ductal ligation surgery. We detected a progressive fibrotic response where both extracellular matrix accumulation and actively remodeled collagen trended upwards at 7 days and significantly increased at 14 days post-ligation. Macrophages, which participate in extracellular matrix remodeling, Gli1-positive and PDGFRα-positive stromal cells, which may deposit extracellular matrix, both increased with ligation. Using single-cell RNA-sequencing, we found that a majority of Gli1-positive cells at embryonic day 16 also express Pdgfra and/or Pdgfrb. However, in adult mice, only a small subset of Gli1+ cells express PDGFRα and/or PDGFRβ at the protein level. Using lineage-tracing mice, we found that Gli1-derived cells expand with ductal ligation injury. Although some of the Gli1 lineage-traced tdTomato-positive cells expressed vimentin and PDGFRβ following injury, there was no increase in the classic myofibroblast marker, smooth muscle alpha-actin. Additionally, there was little change in extracellular matrix area, remodeled collagen area, PDGFRα, PDGFRβ, endothelial cells, neurons, or macrophages in Gli1 null salivary glands following injury when compared with controls, suggesting that Gli1 signaling and Gli1-positive cells have only a minor contribution to mechanical injury-induced fibrotic changes in the salivary gland. We used scRNA-seq to examine cell populations that expand with ligation and/or showed increased expression of matrisome genes. Pdgfra-, Pdgfrb-positive stromal cell subpopulations both expanded in response to ligation, showed increased expression and a greater diversity of matrisome genes expressed, consistent with these cells being fibrogenic. Defining the signaling pathways driving fibrotic responses in stromal cell sub-types could reveal future therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Identifying Fibrogenic Cells Following Salivary Gland Obstructive Injury

Altrieth

O’Keefe

Gellatly

et al. 2023

Preprint

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“…Interestingly, whereas the Pdgfra+ fibroblast-like cluster was broadly negative for Acta2 , we noted a subset of cells that were Acta2 low ( Fig. 2, A and B ), suggesting a cell state transition from fibroblast to myofibroblast, a key step in wound healing ( 19, 35 – 37 ).…”

Section: Resultsmentioning

confidence: 93%

“…19.523242 doi: bioRxiv preprint were Acta2 low (Fig. 2, A and B), suggesting a cell state transition from fibroblast to myofibroblast, a key step in wound healing (19,(35)(36)(37).…”

Section: A Single-cell Rna-sequencing Atlas Of the Mouse Intestinal M...mentioning

confidence: 99%

Origin and adult renewal of the gut lacteal musculature from villus myofibroblasts

Sanketi

Mantri

Tavallaei

et al. 2023

Preprint

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Intestinal smooth muscles are the workhorse of the digestive system. Inside the millions of finger-like intestinal projections called villi, strands of smooth muscle cells contract to propel absorbed dietary fats through the adjacent lymphatic vessel, called the lacteal, sending fats into blood circulation for energy production. Despite this vital function, how villus smooth muscles form, how they assemble alongside lacteals, and how they repair throughout life remain unknown. Here we combine single-cell RNA sequencing of the mouse intestine with quantitative lineage tracing to reveal the mechanisms of formation and differentiation of villus smooth muscle cells. Within the highly regenerative villus, we uncover a local hierarchy of subepithelial fibroblast progenitors that progress to become mature smooth muscle fibers, via an intermediate contractile myofibroblast-like phenotype, a long-studied hallmark of wound healing. This continuum persists in the adult intestine as the major source of smooth muscle reservoir capable of continuous self-renewal throughout life. We further discover that the NOTCH3-DLL4 signaling axis governs the assembly of villus smooth muscles alongside their adjacent lacteal, which is necessary for gut absorptive function. Overall, our data shed light on the genesis of a poorly defined class of intestinal smooth muscle and pave the way for new opportunities to accelerate recovery of digestive function by stimulating muscle repair.

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“…20 ADAMDEC1 is critical in the fibroblastic response to tissue remodeling and healing during colitis 21 and PDGFRA+ fibroblasts display a proliferative phenotype and are a major source of collagen. 22,23 Based on the prominent role of fibroblasts in CDs signaling, the differences largely restricted to the LP1/2 fraction, the over-representation of distinct fibroblast types, and the strong contribution to transcriptional changes in CDs, we sought a unifying molecule and identified CDH11 as the only cell surface receptor shared by the CXCL14+ and MMP/WNT5A+ fibroblasts. While also expressed in macrophages, CDH11 is primarily responsible for mediating homophilic stromal cell-cell interactions, [24][25][26][27] is upregulated in fibrotic disorders of the lung, 24 liver, 25 skin, 26 intestine, 27 and its inhibition attenuates fibrosis in multiple animal models.…”

Section: Discussionmentioning

confidence: 99%

Stricturing Crohn’s disease single-cell RNA sequencing reveals fibroblast heterogeneity and intercellular interactions

Mukherjee

Nguyen

et al. 2023

Preprint

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Background: Fibroblasts play a key role in stricture formation in Crohn's disease (CD), but understanding it's pathogenesis requires a systems-level investigation to uncover new treatment targets. We studied full thickness CD tissues to characterize fibroblast heterogeneity and function by generating the first single cell RNA sequencing (scRNAseq) atlas of strictured bowel and providing proof of principle for therapeutic target validation. Methods: We performed scRNAseq of 13 fresh full thickness CD resections containing non-involved, inflamed non-strictured, and strictured segments as well as 7 normal non-CD bowel segments. Each segment was separated into mucosa/submucosa or muscularis propria and analyzed separately for a total of 138 tissue samples and 409,001 cells. We validated Cadherin-11 (CDH11) as a potential therapeutic target by using whole tissues, isolated intestinal cells, NanoString nCounter, next generation sequencing, proteomics and animal models. Results: Our integrated dataset revealed fibroblast heterogeneity in strictured CD with the majority of stricture selective changes detected in the mucosa/submucosa, but not the muscle layer. Cell-cell interaction modeling revealed CXCL14+ as well as MMP/WNT5A+ fibroblasts displaying a central signaling role in CD strictures. CDH11, a fibroblast cell-cell adhesion molecule, was broadly expressed and upregulated, and its pro-fibrotic function was validated by NanoString nCounter, RNA sequencing, tissue target expression, in vitro gain- and loss-of-function experiments, proteomics, and two animal models of experimental colitis. Conclusion: A full-thickness bowel scRNAseq atlas revealed previously unrecognized fibroblast heterogeneity and interactions in CD strictures and CDH11 was validated as a potential therapeutic target. These results provide a new resource for a better understanding of CD stricture formation and opens potential therapeutic developments.

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Temporal control of PDGFRα regulates the fibroblast-to-myofibroblast transition in wound healing

Cited by 35 publications

References 77 publications

Identifying Fibrogenic Cells Following Salivary Gland Obstructive Injury

Identifying Fibrogenic Cells Following Salivary Gland Obstructive Injury

Origin and adult renewal of the gut lacteal musculature from villus myofibroblasts

Stricturing Crohn’s disease single-cell RNA sequencing reveals fibroblast heterogeneity and intercellular interactions

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