Mechanisms Regulating Stem Cell Function in Health and Disease

HSC development, fate decisions, expansion, and their use in cell and gene therapy

Hematopoietic stem cells (HSCs) sustain hematopoiesis throughout the lifespan of an individual by constantly replenishing the blood with committed hematopoietic progenitor cells (HPCs) and differentiated, mature blood cells. This is achieved through their balance of self-renewal with commitment decisions, which are controlled by complex mechanisms that rely on both the cellular and molecular nature of HSCs, including intrinsic transcriptomic networks and metabolic properties, and the molecular cross-talk that occurs between HSCs and the niches they reside in.
HSC transplantation (HSCT) is a highly utilized therapy for the treatment of a wide range of heritable and acquired disorders of the blood and immune system. The majority of HSCTs use donor allogeneic cells with matching haplotypes to avoid graft versus host disease as well as graft rejection. However, there is a scarcity of donor product for a variety of ethnic groups with rare haplotypes. Thus, the therapeutic potential of HSCs could be significantly broadened by methods that would either enable the ex vivo expansion of bona fide HSCs or the generation of HSCs de novo by reprogramming adult somatic cells.

Specific projects revolve around:

1) Unraveling the cellular and molecular events underlying human HSC engraftment and reconstitution. This project will provide critical direct insights into basic human HSC biology, specifically the dynamic processes and balance of self-renewal, quiescence and cell fate decisions in vivo upon HSC transplantation.

2) Understanding the mechanisms by which human HSCs can be expanded ex vivo without losing their functional properties and to improve, commercialize and bring to the bedside a cellular expansion protocol that utilizes valproic acid (in collaboration with Dr. Ronald Hoffman). This approach is currently being evaluated in a clinical phase I trial (NCT03885947). Ongoing pre-clinical research deals with process and product improvement and cryopreservation of the expanded product with optimal retention of transplantation functionality.

4) Exploring ex vivo HSC expansion with and for gene therapy purposes.

5) Understanding the mechanisms of reprogramming somatic cells into functional hematopoietic stem and progenitor cells.

6) Refining/improving the reprogramming process, so that the generated cells will be capable of sustaining in vivo hematopoiesis, and developing this hematopoietic reprogramming technology into a clinical product for treating blood disorders.

6) Investigating the molecular cross-talk between niche cells and HSCs or cancer cells resulting in specific cell fate decisions such as balance of self-renewal versus commitment, malignant transformation or tumor cell dissemination, i.e., metastasis.

Disease Modeling and Therapeutics with Pluripotent Stem Cells.

Several collaborative projects involve derivation of induced pluripotent stem cells (iPSCs) from clinically healthy individuals and patients with specific syndromes with a focus on familial cancers and cardiovascular disorders (e.g., Marfan Syndrome, Pulmonary Hypertension, Aortic Stiffness), and their use to understand the etiology of disease, to identify novel therapeutic targets, to evaluate existing drugs, the molecular underpinnings of variability in drug responses of individuals, all with the indent to develop precise and personalized treatments for patients.