Yujiro Hayashi, Ph.D.

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SUMMARY

Yujiro Hayashi, Ph.D., conducts research in the areas of physiology, pharmacology, biochemistry, molecular biology and epigenetics of the gastrointestinal (GI) tract. Dr. Hayashi's current focus is on studying the molecular and epigenetic mechanisms underlying gastric pacemaker stem cell aging.

Focus areas

• Recognizing the role of interstitial cells of Cajal (ICC), the pace-maker cells of the GI tract, in diabetic gastric symptoms. Diabetic gastroparesis is a chronic disorder of delayed gastric emptying without mechanical obstruction and a significant therapy-refractory complication of diabetes. Depletion of ICC and reduced KIT signaling are common in diabetic gastroparesis. Dr. Hayashi elucidated the cellular signaling and epigenetic mechanism of action of insulin-like growth factor-1 in stem cell factor (KIT ligand) expression. In contrast to patients with diabetic gastroparesis, in approximately 20% of patients with type 2 diabetes, gastric emptying is accelerated and associated with increased blood levels of glucose. Dr. Hayashi led the first study describing ICC overgrowth and accelerated gastric emptying in Lepr^db/db mice, an established mouse model of type 2 diabetes. This study also defined the hyperglycemia-induced oxidative metabolism that activates the ERK-ETV1-KIT signaling pathway, leading to ICC overgrowth and increasing gastric contraction frequency.
• Defining the role of ICC and ICC stem cells (ICC-SCs) in GI stromal tumors (GISTs). GISTs, the most common human sarcoma, originate from the ICC lineage. Although the majority of GISTs are initially responsive to KIT-platelet-derived growth factor receptor-alpha (PDGFRA) receptor tyrosine kinase inhibitors, such as imatinib (the first line treatment of advanced GISTs), these treatments are not curative due to disease persistence. Dr. Hayashi discovered PDGFRA as a tumor promoter in GISTs and showed that PDGFRA inhibition disrupted the KIT-ERK-ETV1 signaling loop, leading to GIST growth arrest. This study suggests that selective PDGFRA inhibitors such as crenolanib might be used to treat patients with imatinib-resistant KIT mutant GISTs.
• Discovery of the role of ICC and ICC-SCs in GI pathophysiology. ICC loss and dysfunction is associated with GI motor disorders. As in older adults, selective loss of ICC is observed in both the stomach and the intestine of klotho mice, a mouse model of accelerated aging. Reduced food intake, diminished antral pace-making and impaired nitrergic control are associated with gastric ICC loss in klotho mice. Aging-associated depletion of ICC arises from persistent cell cycle arrest of precursors occurring without an increase in canonical senescence markers or apoptosis. The blockade of precursor self-renewal is initiated by unopposed Wnt signaling and mediated by TRP53.
• Therapeutic effects of stem cell transplantation on GI diseases. As a doctoral student, Dr. Hayashi studied the role of bone marrow-derived cells in the GI tract during injury and healing. Dr. Hayashi demonstrated that bone marrow cells with characteristics of mesenchymal stem cells, which can give rise to bone, cartilage or fat cells, accelerated the healing of ulcers following injection in the vicinity of lesions in the stomach and colon of rats. Dr. Hayashi also showed that the beneficial effects of the transplanted stromal cells were due, in part, to their differentiation into a specific cell type and ability to secrete a peptide factor promoting blood vessel formation. As a postdoctoral researcher, he also described therapeutic effects of gastric smooth muscle-derived stem cells (ICC-SCs) in experimental colitis that occur through prostaglandin E₂-mediated immunosuppression.

Significance to patient care

Age-related gastric dysfunction is associated with anorexia underlying sarcopenia and frailty, but the mechanisms of this dysfunction are incompletely understood. ICC — the pacemaker cells of the gastrointestinal tract — and ICC-SCs decline with age. The research of Dr. Hayashi's lab will determine the molecular and epigenetic mechanisms that drive ICC-SC decline, a putative mechanism of ICC loss and age-related gastric dysfunctions. Data obtained from these studies will provide rationale for discovering new therapeutic targets. Furthermore, Dr. Hayashi's lab will introduce the concept of epigenetic control of gene expression as a novel therapeutic target for preventing decline in gastric function that occurs during aging.

Professional highlights

• Recipient, National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases R01 DK121766-01, 2020-present
• Pilot Grant Award, Center for Biomedical Discovery, Mayo Clinic, 2021
• Recipient, Poster of Distinction Award, Digestive Disease Week, 2019
• Recipient, American Gastroenterological Association-Allergan Foundation Pilot Research Award in Gastroparesis, 2018-2019
• Recipient, Young Investigator Award, Digestive Disease Week, 2016
• Recipient, Distinguished Poster Award, Mayo Clinic Center for Signaling in Gastroenterology Annual Minisymposium, 2015
• Participant, Neurogastroenterology and Motility Section Plenary Presentation, Digestive Disease Week, 2014
• Participant, Neurogastroenterology and Motility Section Plenary Presentation, Digestive Disease Week, 2013
• Recipient, Poster of Distinction Award, Digestive Disease Week, 2012
• Recipient, Award of Excellence, Fourth International Pfizer Science and Research Symposium, 2007
• Recipient, Award of Excellence, Second Inflammation Conference in Alimentary Tract, 2007
• Recipient, Travel Award, Asian Pacific Digestive Week, 2007
• Recipient, The Japanese Society of Ulcer Research Award, 2006
• Recipient, Research Scholarship, Japan Student Services Organization, 2003-2008