Microenvironmental Endogenous Reprogramming of Differentiated Smooth Muscle Cells

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DESCRIPTION (provided by applicant): Vascular smooth muscle cells (SMCs) are highly specialized cells that contract to maintain vascular tone, are quiescent and express high levels of SMC-specific proteins, such as smooth muscle myosin heavy chain (SMMHC). Under pathological conditions, however SMCs are capable of undergoing profound phenotypic and functional changes making them major contributors to pathological neointima formation. An important paradigm shift in recent years suggests that vascular progenitor cells (VPCs) with the capacity to differentiate into SMCs and endothelial cells reside in a specialized niche within the adventitia of postnatal vessels. While emerging data support the existence of adventitial VPCs, important unanswered questions remain, including their origin and their contribution to vessel maintenance, repair, and pathological lesion formation. Using an innovative in vivo fate-mapping approach, we made the unanticipated observation that mature SMCs migrate into the adventitia, downregulate SM marker expression, and gain expression of progenitor cell markers. Our preliminary findings demonstrate that a population of SMC-derived Sca1(+) cells can be isolated from adult vessels that express a functional progenitor cell phenotype and exhibit the capacity to differentiate into SMCs. A small percentage retained expression of Sca1, indicating the potential for self-renewal. Our findings suggest the emergence of resident VPCs from reprogrammed mature SMCs. Our overall hypothesis is that mature SMCs migrate to the adventitia during the later stages of vascular development and are reprogrammed to VPCs in response to specific signals expressed exclusively in the adventitia (e.g. microenvironmental reprogramming); reprogramming is dependent on induction on the transcription factor, Klf4. After vascular injury, recruitment of these cells contributes to neointima formation. Such a finding could have a profound impact on defining the molecular mechanisms underlying the formation and maintenance of VPCs and could lead to advances in our understanding of somatic cell reprogramming to improve clinical therapeutic applications. Mature SMCs as the source of resident VPCs is an anti-dogmatic theory that would challenge existing concepts. Two Aims are proposed to establish the importance and the role of SMC-derived AdvSca1 cells in normal vessels and in the setting of vascular injury. In Aim One, we will characterize and define the contribution of mature SMC to the adventitial VPC pool, we will define the in vitro functional characteristics of SMC-derived VPCs, and we will define the in vitro and in vivo role of Klf4 on SMC reprogramming. For Aim Two, we will determine the fate of SMC-derived VPCs in response to wire-induced vascular injury.