Altered control of the differentiated state of the smooth muscle cell (SMC) or "SMC phenotypic switching", is implicated in the pathogenesis of a number of major human diseases including atherosclerosis, hypertension, cancer, and asthma which collectively account for >50% of deaths and health care costs in developed societies. However, our understanding the precise role of SMC phenotypic switching in these diseases, and the mechanisms that control SMC phenotypic switching in vivo have been greatly confounded because this process is characterized by loss of expression of SMC marker genes required to identify the cells, and many SMC genes can be expressed by other cell types. Of major significance, studies employing unique SMC- pericyte (SMC-P) lineage tracing mice developed by the Owens lab provide evidence that: 1) the majority of phenotypically modulated SMC-P within atherosclerotic lesions or models of injury-repair in vivo show no detectible expression of SMC markers and can only be identified using rigorous lineage tracing methods;and 2) SMC-P de-differentiate and give rise to multiple other cell types following naphthalene-induced lung injury wherein they appear to trans-differentiate into non-ciliated lung epithelial (Clara) cells, myocardial infarction (MI) where they become myofibroblasts (MFs), and liver regeneration where they give rise to Kupfer cells and other hepatic cells yet to be identified. Moreover, we have shown that: 1) phenotypic switching of cultured SMC is mediated by activation of the embryonic stem cell (ESC) and induced pluripotential stem (iPS) cell pluripotency factors Oct4 and Klf4;and 2) SMC-P specific conditional Klf4 knockout mice show profoundly impaired cardiac repair following MI. Taken together, results support the hypothesis that perivascular cells represent a source of mesenchymal stem cell (MSC)-like cells that play a key role in tissue regeneration and repair, and that phenotypic transitions of these cells are mediated via stem cell pluripotency gene networks. This hypothesis will be tested by addressing three specific aims.
Aim 1 will test the hypothesis that SMC-Ps activate ESC pluripotency networks and give rise to multiple other cell types in the setting of injury-repair.
Aim 2 will tes the hypothesis that H3K4diMe of SMC marker and regulatory genes not only provides an epigenetic signature of SMC lineage, but also provides a mechanism for "SMC lineage memory" during reversible phenotypic switching following carotid wire injury and that this biases the cells into re-differentiating into a SMC once the vascular repair is complete.
Aim 3 will test the hypothesis that transitions in SMC-P phenotype and/or trans-differentiation to alternative cell types in the setting of injury-repair are dependent on activation of the ESC pluripotency genes Klf4 and Oct4, and are mediated at least in part through epigenetic mechanisms. Studies will define mechanisms that regulate transitions of SMC-P to MSC-like cells in vivo, and may contribute to development of novel therapeutic approaches for enhancing stem cell like properties of SMC-P in vivo to augment tissue repair following injury, and/or to treat a wide plethora of major human diseases.

Public Health Relevance

The studies in this proposal are focused on elucidating mechanisms whereby the cells that surround your blood vessels, i.e. smooth muscle cells (arteries and veins) and pericytes (capillaries), undergo reprogramming to multi-potential stem cell-like state, and trans-differentiate to other cell types during tissue repair and regeneration. Studies may lead to development of novel therapies to enhance the stem cell like properties of these endogenous stem cells to augment tissue repair following injury, and to treat human degenerative diseases including heart failure, Alzheimer's, muscular dystrophy, cancer, chronic obstructive pulmonary disease, and emphysema.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL057353-16
Application #
8499535
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Srinivas, Pothur R
Project Start
1998-04-01
Project End
2017-03-31
Budget Start
2013-06-01
Budget End
2014-03-31
Support Year
16
Fiscal Year
2013
Total Cost
$387,320
Indirect Cost
$142,181
Name
University of Virginia
Department
Physiology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Shankman, Laura S; Gomez, Delphine; Cherepanova, Olga A et al. (2016) Corrigendum: KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat Med 22:217
Gomez, Delphine; Owens, Gary K (2016) Reconciling Smooth Muscle Cell Oligoclonality and Proliferative Capacity in Experimental Atherosclerosis. Circ Res 119:1262-1264
Cherepanova, Olga A; Gomez, Delphine; Shankman, Laura S et al. (2016) Activation of the pluripotency factor OCT4 in smooth muscle cells is atheroprotective. Nat Med 22:657-65
Bennett, Martin R; Sinha, Sanjay; Owens, Gary K (2016) Vascular Smooth Muscle Cells in Atherosclerosis. Circ Res 118:692-702
Cuttano, Roberto; Rudini, Noemi; Bravi, Luca et al. (2016) KLF4 is a key determinant in the development and progression of cerebral cavernous malformations. EMBO Mol Med 8:6-24
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
Shankman, Laura S; Gomez, Delphine; Cherepanova, Olga A et al. (2015) KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat Med 21:628-37
Tabas, Ira; García-Cardeña, Guillermo; Owens, Gary K (2015) Recent insights into the cellular biology of atherosclerosis. J Cell Biol 209:13-22
Nurnberg, S T; Cheng, K; Raiesdana, A et al. (2015) Coronary Artery Disease Associated Transcription Factor TCF21 Regulates Smooth Muscle Precursor Cells that Contribute to the Fibrous Cap. Genom Data 5:36-37
Gomez, Delphine; Swiatlowska, Pamela; Owens, Gary K (2015) Epigenetic Control of Smooth Muscle Cell Identity and Lineage Memory. Arterioscler Thromb Vasc Biol 35:2508-16

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