Randolph Ashton, Ph.D.
Deepak Srivastava, M.D.
Engineering Cell Fate For Human Disease: Lessons from Embryogenesis
Engineering of gene networks that stabilize cell fate and behavior would allow full control over biological process and disease-related changes in cell states. To accomplish this, it is necessary to deeply understand the establishment of normal networks and how they are perturbed in disease. We have focused our efforts on heart disease, a leading cause of death in adults and children. We have described complex signaling, transcriptional and translational networks that guide early differentiation of cardiac progenitors and later morphogenetic events during cardiogenesis. By leveraging these networks, we have reprogrammed disease-specific human cells in order to model genetically defined human heart disease in patients carrying mutations in cardiac developmental genes. These studies revealed mechanisms of haploinsufficiency and we now demonstrate the contribution of genetic variants inherited in an oligogenic fashion in congenital heart disease. We also utilized a combination of major cardiac developmental regulatory factors to induce direct reprogramming of resident cardiac fibroblasts into cardiomyocyte-like cells with global gene expression and electrical activity similar to cardiomyocytes, and have revealed the epigenetic mechanisms underlying the cell fate switch. Most recently, we identified an approach to unlock the cell cycle in adult cardiomyocytes by introducing fetal cyclins and cyclin dependent kinases, and have been able to induce resident, post-mitotic cardiomyocytes to undergo cell division efficiently enough to regenerate damaged myocardium. Knowledge regarding the early steps of cardiac differentiation in vivo has led to effective strategies to generate necessary cardiac cell types for disease-modeling and regenerative approaches, and may lead to new strategies for human heart disease.
Joseph Wu, M.D., Ph.D.
Stem Cells and Genomics for Precision Medicine
Allan Dietz, Ph.D.
Tatiana Segura, Ph.D.
Promoting Tissue Repair with Granular Materials
Nearly all tissues in the body have the capacity to repair through local stem or progenitor cells, but that due to unfavorable environmental conditions during the normal healing process they are not able to do so. Our laboratory investigates hydrogel biomaterials as a way to “unlock” the regenerative capacity of damaged or diseased tissue to promote repair. Porosity is a feature of hydrogel materials that impairs morphogenetic signals irrespective of biochemical composition. For example, vascularization occurs at different rates depending on pore size and inflammation is reduced when a porous material is implanted when compared to a chemically analogous non-porous material. Our laboratory is pioneering work on the use of granular materials, which are composed of particulate matter, as an alternative approach to conventional hydrogels, which are produced from cross linked polymers. Though the particles are generated from the same polymers as the nano-porous material, the bulk hydrogel is formed through assembling a collection of particles. These bulk hydrogels have “pores” or void volumes in between the assembled particles, which are large enough to support cellular infiltration and tissue repair in skin and brain wounds. These granular materials have interesting features such as injectability, forming a jammed structure that conserves spatial positioning of the particles during injection, and the ability to seed cells as the porous scaffold is forming.
Krishanu Saha, Ph.D.
April Pyle, Ph.D.
Development of a CRISPR/Cas9 Therapeutic Platform for DMD using Human Pluripotent Stem Cells
Ipsita Banerjee, Ph.D.
Arshed Quyyumi, M.D.
Circulating Progenitor Cells – Markers of Regenerative Capacity