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Updated: Jul 25, 2026
Directed Differentiation of Primitive and Definitive Hematopoietic Progenitors from Human Pluripotent Stem Cells
Published on: November 1, 2017
Bottlenecks in deriving definitive hematopoietic stem cells from human pluripotent stem cells: a CIRM mini-symposium
Kelly A Shepard1, Sohel Talib2
1California Institute for Regenerative Medicine, San Francisco, California, USA kshepard@cirm.ca.gov.
Insights
Scientists are working to create functional hematopoietic stem cells (HSCs) from pluripotent stem cells (PSCs). Overcoming the "HSC bottleneck" requires understanding HSC development and the factors influencing their behavior.
Area of Science:
- Regenerative Medicine
- Stem Cell Biology
- Hematopoiesis
Background:
- Pluripotent stem cells (PSCs) cannot yet generate fully functional definitive hematopoietic stem cells (HSCs).
- Current PSC-derived HSCs exhibit deficiencies in developmental potential, self-renewal, and engraftment post-transplantation.
- A significant challenge, termed the "HSC bottleneck," hinders the clinical application of PSC-derived HSCs.
Framework:
- A workshop convened by the California Institute for Regenerative Medicine (CIRM) focused on overcoming the HSC bottleneck.
- Key knowledge gaps identified include understanding human HSC ontogeny and the intrinsic/extrinsic factors governing HSC function.
- Prioritizing mechanistic studies in HSC biology is crucial for future research initiatives.
Implementation:
- Development of novel molecular profiling techniques for HSC properties.
- Creation of advanced model systems and assays to predict and evaluate HSC function.
- Advancement of technologies for manipulating cell culture conditions and genetic programs.
Implications:
- Addressing these knowledge gaps is essential for advancing stem cell therapies.
- The workshop provided a clear definition of the HSC bottleneck and its challenges.
- Future research should explore high-risk, high-gain approaches in HSC biology.
Abstract:
On August 29, 2013, the California Institute for Regenerative Medicine (CIRM) convened a small group of investigators in San Francisco, CA, to discuss a longstanding challenge in the stem cell field: the inability to derive fully functional, definitive hematopoietic stem cells (HSCs) from pluripotent stem cells (PSCs). To date, PSC-derived HSCs have been deficient in their developmental potential and their ability to self-renew and engraft upon transplantation. Tasked with identifying key challenges to overcoming this "HSC bottleneck", workshop participants identified critical knowledge gaps in two key areas: (a) understanding the ontogeny of human HSCs, and (b) understanding of the intrinsic and extrinsic factors that govern HSC behavior and function. They agreed that development of new methods and tools is critical for addressing these knowledge gaps. These include molecular profiling of key HSC properties, development of new model systems/assays for predicting and assessing HSC function, and novel technological advancements for manipulating cell culture conditions and genetic programs. The workshop produced tangible advances, including providing a current definition of the nature and challenge of the HSC bottleneck and identifying key mechanistic studies of HSC biology that should be prioritized for future funding initiatives (e.g., including higher risk approaches that have potential for high gain).
