Research Overview

Our group has pioneered in the field of stem cell bioengineering, an area that applies engineering principles to stem cell biology. Our research focuses on understanding how complex communication networks between stem cells and their progeny influence self-renewal and differentiation, and how this information can be applied to the design of novel technologies capable of controlling cell fate. Our work has advanced our understanding of stem cell developmental processes and led to the development of cutting-edge technologies for the growth and differentiation of stem cells. Direct applications of his work include tissue and cellular engineering, gene therapy, and cell transplantation.

Currently we are working on three major projects in our lab:

Blood Stem Cells

Hematopoietic stem cells (HSCs) are the stem cells that give rise to all the other blood cells through the process of haematopoiesis. The clinical utility of HSCs arises from their ability to engraft and sustain multilineage hematopoiesis in compromised hosts. Umbilical cord blood is a very attractive source of HSCs. The major limitation of the use of UCB for hematopoietic transplantation is the limited number of stem and progenitor cells obtained in each UCB collection. We have examined the role of cell population dynamics on HSC expansion of UCB-derived cells, and have developed automated systems to manipulate subpopulations of cells and to control the delivery of soluble proteins to the culture. Our predominant observation from this work is that blood stem cell growth in vitro, and perhaps also in vivo, is limited by feedback networks from differentiated cells.

Pluripotent Stem Cells

Our work is focused on the development of strategies that identify intracellular control points critical to regulating pluripotency and the transition of pluripotent stem cells (PSC) to blood-forming mesoderm. Our work currently focuses on developing spatially-explicit models that quantitatively predict morphogenetic gradients in 2- and 3-dimensionally organized cell populations, increasing the fidelity and power of our in silico predictions to organogenesis. These models will be used to identify the key molecular control points between the regulatory signaling gradients, and the cell fate-determining transcriptional networks, that influence normal and aberrant blood development and differentiation.

Our experimental efforts are focused on the design synthetic niches that promote generation of definitive blood stem cells from hemogenic mesoderm, and mature T-cells from normal and engineered blood progenitors. Niche engineering, the fabrication of controlled cellular microenvironments, has allowed us to mimic the spatial, temporal and biochemical signals occurring during early human development, and to customize bioreactors for blood stem cell propagation. Current efforts are building on these capabilities by adding spatially controlled ligand presentation, and methods from synthetic biology, to enable temporally and spatially controlled manipulations of both cells and their environments. This strategy will also be applied to engineer and produce blood progenitor derived T-cells by constructing an artificial thymic niche. This work allows us to discover new rules governing tissue development and to develop technologies that enhance the yield and function of blood stem cells and their derivatives.

Computational Approaches

We routinely use computational approaches to enhance our abilities to explore and understand stem cell biology and regenerative medicine. Our work combines approaches from computer science and bioinformatics, numerical simulation and visualization, and theoretical science to study basic and applied problems in stem cell biology. We are also attempting to better understand the development of the blood system with the ultimate goal of being able to more efficiently produce particular blood cell types for clinical use. To this end, we have developed a novel computational approach to determine the diffusible ligand-based cell interactions between cells in the blood developmental hierarchy and how those interactions govern how blood stem cells produce all the cell types in the adult hematopoietic system. Finally, we are also interested in how the simulate intracellular gene regulatory networks (GRNs) activation during the maintenance of stem cell pluripotency and for their transition to differentiated cell fates. Ongoing studies are particularly focused on developing spatially-explicit multiscale models of how diffusible factors secreted from individual cells influence surrounding cells, or initiate changes in their gene and signaling networks to induce cell fate transitions.