Deciphering How Tissue Resident Macrophages Regulate Musculoskeletal Regeneration In Spiny Mice

Grants and Contracts Details

Description

One path towards generating new therapeutic avenues to induce regeneration is understanding fundamental differences between a regenerative and scarring response to injury. When tissue regeneration in spiny mice (Acomys) is studied in parallel with rodent models of scarring (e.g., laboratory mice - Mus), this comparative approach can uncover fundamental cell states and molecular signals that explain how identical injuries follow one healing trajectory, instead of the other. At the outset of either healing type, tissue trauma stimulates sterile inflammation that first protects, and then resolves the injury. Inflammation is orchestrated by macrophages whose phenotypic states can have diverse functions. While current data supports that macrophages are required for proper wound healing, whether macrophages specifically regulate musculoskeletal regeneration is poorly understood. The long-term goal of our research is to uncover key molecular signals and cell states that direct mammalian musculoskeletal injuries towards regenerative healing. The objective of this proposal is to understand how tissue resident macrophages (TR-MΦs) and their secreted products specifically regulate regeneration in spiny mice and to manipulate the wound microenvironment in laboratory mice to enhance regenerative healing. The central hypothesis we will test is that TR-MΦs are required separately during the wound healing and tissue generation stages of regeneration to first regulate inflammatory magnitude and oxidative stress, and then to facilitate cell proliferation. This hypothesis is based upon our published and preliminary studies demonstrating that when spiny mouse TR-MΦs are depleted prior to injury, regeneration is inhibited, and Acomys TR-MΦs uniquely produce secreted molecules such as VEGFc and lactoferrin (LTF) that are important for regeneration. Guided by strong preliminary data, this hypothesis will be tested by pursuing the following three specific aims: (1) Asses how TR-MΦs separately regulate cellular inflammation and new tissue formation during regeneration by depleting TR-MΦs in spiny mice and using established assays to assess re-epithelialization, inflammation, extracellular matrix production and proliferation. Single cell RNA-sequencing will also be deployed to analyze how loss of TR-MΦs alters resident cell states and behavior. (2) Define the species-specific epigenetic and transcriptional landscape of TR-MΦs during regeneration (Acomys) versus scar formation (Mus) to discover the genetic program controlling TR-MΦ identity in spiny mice and (3) functionally assess if exogenous lactoferrin can rescue Acomys regeneration in the absence of TR- MΦs and when delivered to mouse injuries, enhance healing. The approach is innovative, in the applicant’s opinion, because it explicitly focuses on understanding how complex tissue regeneration occurs naturally in an adult mammal. The proposed research is significant because it is expected to provide new and fundamental insight into how TR-MΦs regulate musculoskeletal healing and because our discoveries can inform novel clinical interventions to reduce fibrosis and stimulate regeneration.
StatusActive
Effective start/end date3/13/177/31/29

Funding

  • National Institute Arthritis Musculoskeletal & Skin: $609,886.00

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