Vascular smooth muscle cells (SMCs) are highly specialized cells that express high levels of SMC-specific proteins, such as smooth muscle myosin heavy chain (SMMHC/Myh11) and smooth muscle-?ctin (?A/Acta2)1. Under pathological conditions, however, SMCs are capable of undergoing profound phenotypic and functional changes resulting in a proliferative, inflammatory phenotype. An important paradigm shift in recent years suggests that vascular progenitor cells (VPCs) reside in a specialized niche within the adventitia of postnatal vessels. Adventitial VPCs express several stem cell markers, including Sca1 and CD34, have the capacity to differentiate in vitro into multiple lineages in response to specific signals, and potentially contribute to intimal lesions in vivo. However, important unanswered questions remain, including their origin, their degree of pluripotency and/or heterogeneity, and their contribution to vessel maintenance, repair, and pathological lesion formation. Using an innovative in vivo fate-mapping approach to genetically label mature Myh11- expressing SMC, we definitively established that mature SMCs give rise to the majority of intimal SMCs in response to wire-induced injury. Quite unexpectedly, we made the observation that some mature SMCs reverse migrate into the adventitia, exhibit no detectable expression of SM markers, but gain expression of Sca1 and CD34. We established that a distinct subpopulation of AdvSca1 progenitors arise from mature SMCs through a process we are calling endogenous adventitial reprogramming and suggest these cells play important roles in arterial homeostasis and disease. Our preliminary findings suggest SMC-derived AdvSca1 cells reside in the adventitia and contribute to a heterogeneic population of resident VPCs that possess distinct biological properties and fate decisions. Our overall hypothesis is that mature SMCs are reprogrammed during the later stages of vascular development to a subpopulation of functionally distinct VPCs; reprogramming is dependent at least in part on induction of the transcription factor, Klf4 and loss of the tumor suppressor, PTEN. After vascular injury, mobilization and recruitment of these cells contributes to intimal lesion formation and vessel repair. Our data could have a profound impact on defining the endogenous molecular mechanisms underlying the formation and maintenance of resident VPCs, which could lead to the potential to manipulate these cells in situ to improve therapeutic applications in settings suc as atherosclerosis/restenosis, aneurysm formation, ischemic tissues, and tumor angiogenesis. Mature macrovessel SMCs, as the source of resident VPCs, involving more than SMC dedifferentiation, but reprogramming to a functional progenitor phenotype, has not been described.
Three Aims are proposed to define the differentiation potential and response of SMC- derived VPCs to vascular injury (Aim One), to define the role of Klf4 and PTEN on SMC reprogramming and identify essential endogenous pathways involved in SMC reprogramming (Aim Two), and define the in vivo fate and function of SMC-derived VPCs in response to vascular injury (Aim Three).

Public Health Relevance

We demonstrated that a subpopulation of resident vascular progenitor cells (VPCs) that reside in the outer wall of postnatal vessels derive from mature vascular smooth muscle cells that underwent reprogramming to a stem-like phenotype. We will characterize and define the function of these cells and determine the mechanism underlying reprogramming. Our data could have a profound impact on defining the endogenous molecular mechanisms underlying the formation and maintenance of VPCs, which could lead to the potential to activate or repress these cells in situ to improve therapeutic applications.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL121877-03
Application #
9173047
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Olive, Michelle
Project Start
2014-11-15
Project End
2018-10-31
Budget Start
2016-11-01
Budget End
2017-10-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Brewer, Chris M; Majesky, Mark W (2018) Branch Point Smooth Muscle Cells Highlighted by Novel Lineage Tracking Approach. Circ Res 122:194-196
Majesky, Mark W (2018) Vascular Development. Arterioscler Thromb Vasc Biol 38:e17-e24
Berthiaume, Andrée-Anne; Hartmann, David A; Majesky, Mark W et al. (2018) Pericyte Structural Remodeling in Cerebrovascular Health and Homeostasis. Front Aging Neurosci 10:210
Majesky, Mark W; Horita, Henrick; Ostriker, Allison et al. (2017) Differentiated Smooth Muscle Cells Generate a Subpopulation of Resident Vascular Progenitor Cells in the Adventitia Regulated by Klf4. Circ Res 120:296-311
Weiser-Evans, Mary C M (2017) Smooth Muscle Differentiation Control Comes Full Circle: The Circular Noncoding RNA, circActa2, Functions as a miRNA Sponge to Fine-Tune ?-SMA Expression. Circ Res 121:591-593
Wu, Jing; Montaniel, Kim Ramil C; Saleh, Mohamed A et al. (2016) Origin of Matrix-Producing Cells That Contribute to Aortic Fibrosis in Hypertension. Hypertension 67:461-8
Majesky, Mark W (2016) Vascular Smooth Muscle Cells. Arterioscler Thromb Vasc Biol 36:e82-6
Majesky, Mark W (2015) Adventitia and perivascular cells. Arterioscler Thromb Vasc Biol 35:e31-5