Dysfunctions of smooth muscle cells (SMCs) are associated with hypertrophy, hyperplasia and fibrosis found in SM diseases including gastrointestinal (GI) bowel obstruction and Hirschprung's disease. Defective SMCs are dedifferentiated cells that have lost their contractile phenotype. The phenotypic change of SMCs to non- functional dedifferentiated cells has been discovered in vascular injuries ~50 years ago, but the phenotypic and genetic identity of the transformed cells are still unknown. We have found that the transformed cells in the hypertrophic small intestine are myofibroblast like cells that weakly express platelet-derived growth factor receptor alpha and beta (PDGFRa/) (called PDGFRalowhigh cells). We have isolated differentiated PDGFRahigh cells and SMCs from colon and jejunum, and obtained genome scale gene expression profiles. By analyzing the transcriptomes, we identified SMC-specific transcription factors including SRF and MYOCD. Moreover, we found that the phenotype of SMCs is regulated by SRF and an epigenetic modulator DNA methyltransferase 1 and 3a (DNMT1/3a). The present project seeks to uncover a cellar and genetic mechanism for understanding how SMCs are dedifferentiated during the development of intestinal SM hypertrophy and how dedifferentiated cells are redifferentiated into SMCs during the recovery process. Furthermore, this project aims to isolate dedifferentiated cells, establish a cell line in culture, and genetically engineer SMCs from the cell line using SMC-specific transcription factors and the epigenetic regulator DNMT1/3a. To achieve these aims, we have formed a collaborative, multi-institutional research team with Drs. Seungil Ro (PhD, PI), Moon young Lee (MD/PhD, studying the plasticity of SMCs in the hypertrophic condition), a to-be-hired postdoc (PhD, studying the engineering of SMCs from PDGRFalow cells), Douglas Redelman (PhD, cell isolation), Gabsang Lee (PhD/DVM, cell line establishment), Terence Smith (PhD, calcium imaging), Laren Becker (MD/PhD, tissue supply and consulting), Kent Sasse (MD, tissue supply), and Joseph Miano and Kenton Sanders (PhDs, research tool supply and project consulting). These studies will significantly advance our understanding on the phenotypic transition of SMCs at the transcriptome level and could offer a human SMC line for clinical use to repair damaged or non-functional SMCs found in GI SM diseases.

Public Health Relevance

Dysfunction of smooth muscle cells (SMCs) is associated with gastrointestinal motility disorders, but the cellular and molecular mechanism of this SMC dysfunction is unknown. This study seeks to uncover such a mechanism and to engineer functional SMCs by restoring the mechanism in culture.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Greenwel, Patricia
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University of Nevada Reno
Schools of Medicine
United States
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Jorgensen, Brian G; Berent, Robyn M; Ha, Se Eun et al. (2018) DNA methylation, through DNMT1, has an essential role in the development of gastrointestinal smooth muscle cells and disease. Cell Death Dis 9:474
Ha, Se Eun; Lee, Moon Young; Kurahashi, Masaaki et al. (2017) Transcriptome analysis of PDGFR?+ cells identifies T-type Ca2+ channel CACNA1G as a new pathological marker for PDGFR?+ cell hyperplasia. PLoS One 12:e0182265
Lee, Moon Young; Ha, Se Eun; Park, Chanjae et al. (2017) Transcriptome of interstitial cells of Cajal reveals unique and selective gene signatures. PLoS One 12:e0176031
Lee, Moon Young; Park, Chanjae; Ha, Se Eun et al. (2017) Serum response factor regulates smooth muscle contractility via myotonic dystrophy protein kinases and L-type calcium channels. PLoS One 12:e0171262
Ro, Seungil (2016) Multi-phenotypic Role of Serum Response Factor in the Gastrointestinal System. J Neurogastroenterol Motil 22:193-200
Park, C; Lee, M Y; Slivano, O J et al. (2015) Loss of serum response factor induces microRNA-mediated apoptosis in intestinal smooth muscle cells. Cell Death Dis 6:e2011
Park, Chanjae; Lee, Moon Young; Park, Paul J et al. (2015) Serum Response Factor Is Essential for Prenatal Gastrointestinal Smooth Muscle Development and Maintenance of Differentiated Phenotype. J Neurogastroenterol Motil 21:589-602