hiPSC Modeling of Lineage-Specific Smooth Muscle Cell Defects Caused by TGFBR1A230T Variant, and its Therapeutic Implications for Loeys-Dietz Syndrome
Running Title: Zhou et al.; hiPSC Modeling of Loeys-Dietz Syndrome
Dong Zhou, BS1,2+; Hao Feng, BS1,2+; Ying Yang, PhD1; Tingting Huang, BS1,2; Ping Qiu, PhD1; Chengxin Zhang, PhD3; Timothy R. Olsen, PhD4; Jifeng Zhang, PhD5; Y. Eugene Chen, MD, PhD1,5*; Dogukan Mizrak, PhD1*; Bo Yang, MD, PhD1*
1Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI; 2Xiangya School of Medicine, Central South University, Changsha, PRC; 3Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI; 4Department of Systems Biology, Columbia University, New York, NY; 5Department of Internal Medicine, University of Michigan, Ann Arbor, MI
+These authors contributed equally to this work.
Overview
This paper uses a single human mutation in TGFBR1 to study how the mutation may cause the condition. These studies were conducted within a cell culture system. The study employed state-of-the-art technologies such as human-induced pluripotent stem cells and CRISPR-Cas 9 gene editing. It involved changing human stem cells into important cell types (vascular smooth muscle cells derived from cardiovascular progenitor cells found in aortic root and vascular smooth muscle cells derived from neural crest stem cells found in the ascending aorta). This study used both normal and TGBR1 mutated human pluripotent stem cells to develop into the different cell types found in the aorta, understand where and when normal cell function was impaired, and then allowed for experimental rescue with different therapies. It was found that the mutation used resulted in impaired smooth muscle contractile functioning (cells that cause aorta to contract) in only cardiovascular progenitor cells (and not in neural crest stem cells). Treatment of mutated cell types with Activin A (a growth hormone in the TGFB superfamily) and rapamycin (an antifungal metabolite that is inhibitor of a serine/threonine kinase) significantly improved the contractrile abilities in the cardiovascular progenitor cells which may be considered as a potential pharmacological strategy.
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