Olga Cherepanova Laboratory

Research

Research

 Ongoing projects include:  

1.            Novel role of the OCT4/ABCG2 axis in endothelial cells (EC). There is a growing interest in the pluripotency factors (OCT4, KLF4, c-MYC, and SOX2) required for reprogramming somatic cells into iPS cells, a discovery that won Dr. Yamanaka the Nobel Prize in 2012. Until recently, the reactivation of the embryonic stem cell pluripotency factor OCT4 in somatic cells had been a highly controversial topic. Using EC-specific Oct4 knockout mice, we found that OCT4 plays an atheroprotective role (Shin et al., 2022, Cardiovascular Research) and an angiogenesis-regulating role (unpublished data) in EC by regulating EC phenotypic transitions and metabolism. Specifically, we found that OCT4 directly regulates ABCG2 heme and xenobiotic transporter in EC. We use an innovative combination of in vivo EC-lineage tracing and state-of-the-art scRNA-sequencing to elucidate further molecular mechanisms responsible for the OCT4- and ABCG2-dependent athero-protection. Surprisingly, we also discovered the sex-dependent effects of OCT4 in EC and are currently expanding this project to reflect this new direction.  

2.            Toll-like receptor 4 (TLR4) in smooth muscle cell (SMC) phenotypic transitions. Before coming to Cleveland Clinic, Dr. Cherepanova published a Nature Medicine paper showing that genetic inactivation of the pluripotency factor OCT4 in SMC exacerbates atherosclerosis in the Apoe knockout mouse model. It was the first direct evidence of the functional role of OCT4 in any somatic cells. She also found an intriguing connection between OCT4 and innate immunity in that OCT4 and TLR4 regulate each other, which led to a new hypothesis that TLR4 signaling mediates atheroprotective changes in SMC by regulating levels of the pluripotency factor OCT4 via a feedback mechanism.  

3.            Role of the Endothelial-to-Mesenchymal transition in atherosclerosis. Recent EC lineage tracing studies demonstrated that during the development of atherosclerosis, EC undergo an Endothelial-to-Mesenchymal (Endo-MT) transition that is characterized by a change in EC morphology, loss of EC-specific proteins, and activation of Endo-MT markers such as mesenchymal and SMC markers. However, there is currently no clear answer to whether Endo-MT causes disease progression or is a part of the atheroprotective response. Using a novel, innovative dual lineage tracing mouse model designed and generated in our lab, we try to understand the role and extent of Endo-MT in atherosclerosis and other cardiovascular pathologies. 

Selected Publications

View publications for Olga Cherepanova, PhD
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HIGHLIGHTED PUBLICATIONS

Mahajan A, Hong J, Krukovets I, Shin J, Tkachenko S, Espinosa-Diez C, Owens G, Cherepanova OA. Integrative analysis of the lncRNA-miRNA-mRNA interactions in smooth muscle cell phenotypic transitions. Front. Genet, 2024. doi.org/10.3389/fgene.2024.1356558  

Shin J, Hong J, Edwards-Glenn J, Krukovets I, Tkachenko S, Adelus ML, Romanoski CE, Rajagopalan S, Podrez E, Byzova VT, Stenina-Adongravi O, Cherepanova OA. Unraveling the Role of Sex in Endothelial Cell Dysfunction: Evidence From Lineage Tracing Mice and Cultured Cells. ATVB, 2024. doi.org/10.1161/ATVBAHA.123.319833

Shin J, Tkachenko S, Gomez D, Tripathi R, Owens GK, Cherepanova OA. Smooth muscle cell-specific loss of OCT4 accelerates neointima formation after acute vascular injury. Front Cardiovasc Med, 2023, 10. doi.org/10.3389/fcvm.2023.1276945

Zhang L, Altemus J, Ding L, Cherepanova OA, Byzova TV, Podrez EA. Enhanced Akt3 kinase activity reduces atherosclerosis in hyperlipidemic mice in a gender-dependent manner. J Biological Chemistry, 2023. doi.org/10.1016/j.jbc.2023.105425

Shin J, Tkachenko S., Chaklader M. Pletz C, Singh K., Bulut G., Han Y-m, Mitchell K., Baylis R., Kuzmin AA., Hu B., Lathia JD., Stenina-Adognravi O., Podrez E., Byzova T., Owens GK., Cherepanova OA. Endothelial OCT4 is atheroprotective by preventing metabolic and phenotypic dysfunction. Cardiovasc Res, 2022. doi: 10.1093/cvr/cvac036

Gole S, Tkachenko T, Masannat T, Baylis RA, Cherepanova OA. Endothelial-to-Mesenchymal transition in atherosclerosis: Friend or Foe? Cells, 2022. DOI: 10.3390/cells11192946

Cherepanova OA*, Byzova TV*. Pentose phosphate pathway drives vascular maturation. Nat Metab, 2022, doi.org/10.1038/s42255-021-00512-6

Newman AAC, Serbulea V, Baylis RA, Shankman LS, Bradley X, Alencar GF, Owsiany K, Deaton RA, Karnewar S, Shamsuzzaman S, Salamon A, Reddy MS, Guo L, Finn A, Virmani R, Cherepanova OA, Owens GK. Multiple cell types contribute to the atherosclerotic lesion fibrous cap by PDGFRβ and bioenergetic mechanisms. Nat Metab, 2021. DOI: 10.1038/s42255-020-00338-8

Bulut GB, Alencar GF, Owsiany KM, Nguyen AT, Karnewar S, Haskins RM, Waller LK, Cherepanova OA, Deaton RA, Shankman LS, Keller R, Owens GK. KLF4 (Kruppel-Like Factor 4)-Dependent Perivascular Plasticity Contributes to Adipose Tissue inflammation. ATVB, 2021. DOI: 10.1161/ATVBAHA.120.314703

Liu H, Zhu L, Dudiki T, Gabanic B, Good L, Podrez EA, Cherepanova OA, Qin J, Byzova TV. Macrophage Migration and Phagocytosis Are Controlled by Kindlin-3's Link to the Cytoskeleton. J Immunology, 2020. DOI: 10.4049/jimmunol.1901134

Cherepanova OA*, Srikakulapu P, Greene ES, Chaklader M, Haskins RM, McCanna ME, Bandyopadhyay S, Ban B, Leitinger N, McNamara CM, Owens GK*. Novel autoimmune IgM antibody attenuates atherosclerosis in IgM deficient low-fat diet-fed, but not Western diet-fed Apoe–/– mice. ATVB 2020. DOI: 10.1161/ATVBAHA.119.312771                                                                                       

Kuzmin AA, Ermakova VV, Sinenko SA, Ponomartzev SV, Starkova TY, Skvortsova EV, Cherepanova OA, Tomilin AN. Genetic tool for fate mapping Oct4 (Pou5f1)-expressing cells and their progeny past the pluripotency stage. Stem Cell Res Ther. 2019. doi.org/10.1186/s13287-019-1520-6  

Hess DL, Kelly-Goss MR, Cherepanova OA, Nguyen AT, Baylis RA, Tkachenko S, Annex BH, Peirce SM, Owens GK. Perivascular cell-specific knockout of the stem cell pluripotency gene Oct4 inhibits angiogenesis. Nat Comm, 2019. DOI: 10.1038/s41467-019-08811-z                             

Newman AAC, Baylis RA, Hess DL, Griffith SD, Shankman LS, Cherepanova OA, Owens GK. Irradiation abolishes smooth muscle cell investment into vascular lesions in specific vascular beds. JCI Insight, 2018. DOI: 10.1172/jci.insight.121017  

Murgai M, Ju W, Eason W, Kline J, Beury D, Kaczanowska S, Miettinen M, Kruhlak M, Lei H, Shern JF, Cherepanova OA, Owens GK, Kaplan RN. KLF4-dependent perivascular plasticity mediates pre-metastatic niche formation and metastasis. Nat Med, 2017. doi.org/10.1038/nm.4400  

Durgin B, Cherepanova OA, Gomez D, Karaoli T, Alencar GF, Butcher J, Zhou Y-Q, Bendeck M, Isakson B, Owens GK, Connelly JJ. Smooth muscle cell-specific deletion of Col15a1 unexpectedly leads to impaired development of advanced atherosclerotic lesions. AJP Heart, 2017. DOI: 10.1152/ajpheart.00029.2017

Cherepanova OA, Gomez D, Shankman LS, Swiatlowska P, Williams J, Sarmento OF, Alencar FG, Bevard MH, Greene ES, Murgai M, Turner SD, Geng Y-J, Bekiranov S, Connelly JJ, Tomilin A, Owens GK. Activation of the pluripotency factor OCT4 in smooth muscle cells is atheroprotective. Nat. Med, 2016. DOI: 10.1038/nm.4109  

Shankman LS, Gomez D, Cherepanova OA, Salmon M, Alencar FG, Haskins RH, Swiatlowska P, Newman AAC, Greene ES, Straub AC, Isakson B, Randolph GJ, Owens GK. KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat Med 2015. DOI: 10.1038/nm.3866