The mast-cell-specific Mrgprb2 signaling in wound healing and scar formation

Human skin scarring after trauma or surgery remains a major medical problem. The transformation of fibrotic healing processes into regenerative ones, in which original tissues are restored, would constitute an enormous advancement in human health. Unfortunately, effective treatments to reduce scarring are still lacking. Addressing the complex post-injury immune responses is critical to devising effective therapies for skin wound scarring. Our overarching goal is to elucidate a novel wound-healing mechanism that could achieve “scar-free regeneration” in humans. Mast cells (MCs) are the first responders to local skin injury. Recent studies unraveled a unique property of MCs: their IgE-independent activation through the Mas-related G-protein-coupled receptor (Mrgpr)- b2. Mrgprb2 has been previously shown to mediate neurogenic inflammation and post-operative pain in injured skin. Our preliminary data further suggest a role for this novel non-canonical MC signaling (Mrgprb2 and its human homolog MRGPRX2) in wound healing and scar formation. This research will investigate three Specific Aims to test our central hypothesis that Mrgprb2 signaling in connective tissue MCs is a key contributor to post- injury scar formation through its immunoregulatory activities. In Aim 1 (in vivo studies), using Mrgprb2 gene- modified mouse lines, we will test the effects of manipulating Mrgprb2 signaling on skin scarring and regeneration. Mechanistically, we will dissect the pro-inflammatory and pro-fibrotic properties of Mrgprb2 signaling in wound healing animal models. In Aim 2 (in vitro studies), using skin wound-related cells derived from both mice and humans, we will test the hypothesis that Mrgprb2/X2-activated MCs drive immune cell polarization, endothelial- to-mesenchymal transition, and fibroblast proliferation and migration. We aim to decipher human MRGPRX2- regulated cellular interactions as key mechanisms of MC-driven fibrosis. In Aim 3 (human tissue studies), we will ultimately determine effects of MRGPRX2 signaling in human scar tissues using samples collected in the dermatology and plastic surgery clinics. We will also employ ex vivo human skin wound models to test MRGPRX2 signaling in early healing processes. This proposal is innovative because it will unravel a unique mechanistic link between inflammation and fibrosis by elucidating the essential roles of Mrgprb2/X2 signaling in tissue remodeling. The proposed research is significant because it may help develop novel immunological therapies based on using MC-specific GPCR as a target for tissue regeneration in fibrotic diseases of skin. Project Number: 1R01GM153722-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Qing Lin | Institution: OHIO STATE UNIVERSITY, Columbus, OH | Award Amount: $303,082 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 ISB-D (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11048010