HPSCs and Hematopoiesis: From Development to Stem Cell Therapies

Gay M. Crooks, MD
Professor of pathology and laboratory medicine at the University of California, Los Angeles
Christopher M. Sturgeon, PhD
Associate professor of cell developmental and regenerative biology and medicine in the department of hematology and medical oncology at Icahn School of Medicine at Mount Sinai

As part of this year’s Scientific Program, Gay M. Crooks, MBBS, and Christopher M. Sturgeon, PhD, are co-chairing a session that will review human pluripotent stem cell (PSC)–derived hematopoiesis and look at what the future holds for harnessing this technology. Dr. Crooks and Dr. Sturgeon spoke with ASH Clinical News about the Scientific Spotlight Session, “Human Pluripotent Stem Cell–Derived Hematopoiesis: From Development to Stem Cell Therapies.”

Why was this topic selected for a spotlight session? What are the newest developments in the understanding of human PSC-derived hematopoiesis?

Dr. Crooks: As the title suggests, the session is all about hematopoiesis, or the production of blood from human PSCs. These are cells that can make any type of tissue including all blood cell lineages. They can also self-renew, meaning that they are a limitless source of cells. This session will explore how blood forms from PSCs, with a particular focus on cells of the immune system such as T cells or natural killer (NK) cells, either of which can be used in immunotherapy.

Chimeric antigen receptor (CAR) T-cell therapies have shown strong success against certain leukemias, lymphomas, and myelomas but, so far, have depended on engineering autologous T cells harvested from patients. To overcome the cost and inconsistency of the process, researchers have been exploring ways to use T cells or NK cells that can be generated from a self-renewing source – in other words, a product that could be used for multiple patients that does not come from each individual patient.

Can you give us a preview of the session – what topics will you be discussing?

Dr. Crooks: I’ll be talking about how far the field has come in finding ways to produce T cells from HPSCs for therapy. After many years of study, great progress has been made, but challenges remain that come from some of the basic features of T-cell development. I’ll be talking about the latest science to make off-the-shelf T cells from a universal source of PSCs and the use of gene-editing to remove the risk of graft-versus-host disease and rejection of these allogeneic products.

Dr. Sturgeon: I will be discussing our efforts at understanding how human PSCs recapitulate the hematopoietic developmental programs that are found in the mammalian embryo. There are multiple “waves” of blood progenitor production during early embryogenesis, many of which do not give rise to hematopoietic stem/progenitor cells (HSPCs), but instead solely give rise to restricted hematopoietic progenitor cells (HPCs). It’s a broad and still incomplete field of study for developmental biologists. We do know, though, that, for example, in the yolk sac there are at least two waves of HSC-independent production, namely the “primitive” and “EMP (erythro-myeloid progenitor)” waves.  Similarly, in the embryo proper, there are multiple sites of hematopoietic development, with the best characterized location being the dorsal aorta, which we now know harbors at least two distinct progenitors – one that gives rise to multipotent HPCs and the other to HSPCs.

I mention all this because my lab is particularly interested in how to specify each of these programs and obtain only one of these in a culture dish, permitting us to study it in high detail. To that end, we have developed methods to specify exclusively primitive, EMP, and an HPC progenitor that resembles an intra-embryonic origin, all from human PSCs.

How will this information affect clinical practice?

Dr. Sturgeon: I think it is still premature to discuss the clinical impact, but we are now gearing up to test these different NK cell populations, each from different developmental origins, in a preclinical mouse model. Given the in vitro properties of the EMP-like NK cells, it’s very tempting to speculate that they may innately harbor a greater ability to kill tumor cells. Maybe this will tell us that, outside of genetic engineering strategies, human PSCs might be a unique source of progenitors that we simply cannot access in traditional adult donors, because we are tapping into a developmental program that only exists in the early embryo.

Dr. Crooks: Anyone working with CAR T cells right now knows how well they can work, but they also know that there are a lot of practical issues in using them. They are expensive and they are not easily available to all patients. Also, although there have been great results in patients with refractory disease, many patients still have disease relapse after CAR T-cell therapy. For the near future, we are creating systems that mimic the thymus where T cells are normally produced and applying exciting gene-editing methods to modify the process of differentiation. As always, the key is understanding the biology.

What do you think the key takeaways from this session will be for attendees?

Dr. Sturgeon: An important takeaway from the work I will discuss is that, while human PSCs can give rise to NK cells, the fact that the differentiation conditions employed to obtain CD34+ progenitor cells is being overlooked, and can have a large impact on the functional properties of those NK cells.

Dr. Crooks: I hope attendees understand that the field of CAR T-cell therapy or, even more broadly, immune cell therapy, is moving very fast. CAR T-cell therapy is very new, but rapidly changing in terms of what will be available in the next few years for clinical use. Changes are coming.