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.
Status | Active |
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Effective start/end date | 3/13/17 → 7/31/29 |
Funding
- National Institute Arthritis Musculoskeletal & Skin: $609,886.00
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