Piezo inhibition preventsandrescues scarring by targeting the adipocyte to fibroblast transition

Abstract

While past studies have suggested that plasticity exists between dermal fibroblasts and adipocytes, it remains unknown whether fat actively contributes to fibrosis in scarring. We show that adipocytes convert to scar-forming fibroblasts in response to Piezo-mediated mechanosensing to drive wound fibrosis. We establish that mechanics alone are sufficient to drive adipocyte-to-fibroblast conversion. By leveraging clonal-lineage-tracing in combination with scRNA-seq, Visium, and CODEX, we define a mechanically naive fibroblast-subpopulation that represents a transcriptionally intermediate state between adipocytes and scar-fibroblasts. Finally, we show that Piezo1 or Piezo2-inhibition yields regenerative healing by preventing adipocytes activation to fibroblasts, in both mouse-wounds and a novel human-xenograft-wound model. Importantly, Piezo1-inhibition induced wound regeneration even in pre-existing established scars, a finding that suggests a role for adipocyte-to-fibroblast transition in wound remodeling, the least-understood phase of wound healing. Adipocyte-to-fibroblast transition may thus represent a therapeutic target for minimizing fibrosis via Piezo-inhibition in organs where fat contributes to fibrosis.

A tension offloading patch mitigates dermal fibrosis induced by pro-fibrotic skin injections

“…(43) The implication of adipocyte-related pathways in the putatively pro-fibrotic myeloid cluster (Fig. 3E) may also be of interest: fat and fibroblasts/fibrosis are increasingly understood to have an intimate relationship; (40,44,45) lipid dysregulation is common at insulin injection sites and often co-occurs with fibrosis;(4-6) and we have previously postulated that, given current knowledge about the relationship between mechanical forces and adipocytes, tension offloading could be beneficial for both fibrosis and lipodystrophy in the setting of insulin use. (2) Conversely, other cell crosstalk pathways enriched in PP skin have been implicated by other studies as involved in tissue repair and/or possibly anti-fibrotic, including HGF, (46,47) occludin (OCLN), (48) and GDF.…”

“…To address this question, we employed a human foreskin xenograft model, which we have previously validated and used to study the effects of potential anti-fibrotic interventions. (36,40) We engrafted human foreskin samples onto the dorsum of immune-deficient mice (CD-1 nude -to prevent graft rejection), as previously reported, (36) then subjected xenografts to repeated injections of bleomycin with or without adjunct injections of recombinant IL4 protein; other grafts were made and not injected with bleomycin, as an UW/non-fibrotic control (Fig. 4A-B).…”

Tissue fibrosis associated depletion of lipid‐filled cells

“…Emerging evidence in a rigorous study from the Longaker group show that mechanical cues are sufficient for this transition in mouse and human adipocytes. They found Piezo‐1/2 stretch channels in vivo are required for this transition during wound healing and promotes diminished scarring/regenerative healing in skin 148 . They also demonstrate that a subpopulation of dermal adipocytes can convert and clonally expand to profibrotic fibroblasts.…”

“…Adipocyte to fibroblast lineage transition can be tracked faithfully by inducible genetic lineage tracing in mouse skin, determined by the reduced expression of adipocyte marker Perilipin 1 (Plin1) and increased expression of alpha‐SMA (Acta2). Furthermore, lineage traced mature adipocytes can undergo dramatic morphological changes towards a dermal fibroblast phenotype 64,88,148 . The Rinkevich lab has challenged the conversion of lineage traced mature dermal adipocyte to profibrotic fibroblast at a functional level.…”

Pleiotropic physiological functions of Piezo1 in human body and its effect on malignant behavior of tumors

“…For wound healing, the mechanical sensing mediated by Piezo1 drives the transformation of fat cells into fibroblasts that form scars, thereby promoting wound fibrosis. Inhibiting Piezo1, in turn, could target the transformation of fat cells into fibroblasts to prevent and reduce scarring ( Griffin et al, 2023 ). Recent studies have also found that Piezo1 channels play an important role in pain perception.…”