Fibroadipogenic progenitor cells as drivers of angiogenesis during muscle regeneration

摘要

ABSTRACT Skeletal muscle comprises nearly half of body mass and is subject to traumatic injuries, particularly of the extremities. Damaged muscle mass and function must be restored promptly to minimize physical distortion and prevent long-term disabilities. Furthermore, poor outcomes impose significant emotional and financial burdens on affected individuals and their families. An aspirational goal of the NICHD is to advance the ability to regenerate human limbs by using emerging technologies to activate the body’s own growth pathways and processes. Under most circumstances damaged muscle is efficiently regenerated through a coordinated multicellular response involving muscle stem cells (satellite cells, SCs), endothelial cells (ECs), and fibroblasts or fibroadipogenic precursor cells (FAPs) as well as other resident and infiltrating cell types. However, after the loss of tissue over a critical threshold (volumetric muscle loss, VML), tissue regeneration does not occur and neither mass nor function are regained. The molecular and cellular mechanisms underlying the distinction between subthreshold, regenerating wounds vs. nonregenerating VML are not yet sufficiently understood, posing a critical roadblock to development of translational interventions. A novel punch biopsy model of injury and regeneration developed in the PI’s laboratory using the mouse gluteus maximus muscle highlights the sequential activity of FAPs, ECs, and SCs in successful muscle regeneration. A key observation is that if local FAPs are removed, both angiogenesis and myogenesis fail to occur, making the subthreshold injury instead resemble VML. Whether FAPs effect this relationship by direct actions on ECs, myogenic cells, or both is unknown. Therefore, this research project proposes to: 1) confirm the requirement for FAPs in permitting healing of a subcritical VML injury; 2) test the ability of a candidate molecule, periostin, to rescue microvascular and myofiber regeneration in wounds lacking FAPs; 3) determine whether periostin signals directly to ECs, myogenic cells, or both; and 4) perform an unbiased proteomic screen for additional signaling molecules either secreted directly by FAPs or induced in ECs or myogenic cells by FAPs that may promote the regeneration of intact muscle. These experiments will leverage the team's collective expertise in microvascular imaging, muscle regeneration, FAPs biology, and biomaterials to identify, characterize, and functionally test key cellular and molecular factors differentiating between muscle injuries which heal successfully and those which cannot. If successful, this research project will identify molecules and methods which have the potential to be translated into therapies designed to improve clinical outcomes for disabled individuals, thereby addressing a key unmet need in both basic and applied muscle biology.