BME Seminar Series: Dr. Dhvanit Shah, Nationwide Children's Hospital

​Dhvanit I. Shah, Ph.D.

Associate Professor of Pediatrics

St. Baldrick's Foundation Scholar

Center for Childhood Cancers and Blood Diseases

Nationwide Children's Hospital &

The Ohio State University College of Medicine

"Developement of a bioreactor to stimulate hematopoietic stem cell formation"

 

The birth and development of hematopoietic stem cells (HSCs) remain a mystery. During fetal development, a subset of endothelial cells transitions to become HSCs in the aorta-gonad-mesonephros (AGM) region1-3.  Blood flow-mediated shear stress and the activation of nitric oxide synthase (NOS) stimulate the endothelial-to-HSC transition in the AGM4,5. However, we showed thatmalbec (mlbbw306), a zebrafish mutant for cadherin 5, produces HSCs despite circulation arrest6 and the inhibition of NOS, suggesting that other biomechanical forces, mechanosensation pathways, or epigenetic mechanisms might regulate HSC formation and have utility in developing HSCs. Here we show that Piezo1-sensitive biomechanical stretching of hemogenic endothelial cells enhances Dnmt3b expression for long-term (LT)-HSC formation. The cdh5-morphant (MO) embryos have heartbeat-mediated pulsation in blood vessels without cardiac output and active blood flow. Pulsation-derived stretching activates Piezo1 mechanosensitive channels that further enhancesDnmt3b expression in the AGM to stimulate the endothelial-to-HSC transition. The simulation of pulsation or the pharmacological activation of Piezo1 also yields three times the amount of LT-HSCs, which reconstitute to normal, functional multi-lineage adult blood upon serial transplantation. Our results demonstrate how pulsation-mediated biomechanical forces stimulate cell-fate transitions and stem cell formation by activating mechanosensitive channels as well as epigenetic machinery. We present a model that addresses major challenges in HSC transplantation and cellular therapies for treating blood and bone marrow diseases.  In addition, we report a scalable bioreactor with potential widespread use and a pharmacological target to develop and expand LT-HSCs.