Dissociation of Survival, Proliferation, and State Control in Human Hematopoietic Stem Cells

• Published in: Stem cell reports 2017-01, Vol.8 (1), p.152-162
• Main Authors: Knapp, David J.H.F., Hammond, Colin A., Miller, Paul H., Rabu, Gabrielle M., Beer, Philip A., Ricicova, Marketa, Lecault, Véronique, Da Costa, Daniel, VanInsberghe, Michael, Cheung, Alice M., Pellacani, Davide, Piret, James, Hansen, Carl, Eaves, Connie J.
• Format: Article
• Language: English
• Subjects: Animals; apoptosis; Biomarkers; cell death; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; growth factor; hematopoietic stem cell; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; HSC; human; Humans; In Vitro Techniques; Integrin alpha6 - metabolism; Intercellular Signaling Peptides and Proteins - pharmacology; Mice; microfluidics; mitogenesis; Phenotype; proliferation; self-renewal; survival; transplantation; xenotransplantation
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2016.12.003

The role of growth factors (GFs) in controlling the biology of human hematopoietic stem cells (HSCs) remains limited by a lack of information concerning the individual and combined effects of GFs directly on the survival, Mitogenesis, and regenerative activity of highly purified human HSCs. We show that the initial input HSC activity of such a purified starting population of human cord blood cells can be fully maintained over a 21-day period in serum-free medium containing five GFs alone. HSC survival was partially supported by any one of these GFs, but none were essential, and different combinations of GFs variably stimulated HSC proliferation. However, serial transplantability was not detectably compromised by many conditions that reduced human HSC proliferation and/or survival. These results demonstrate the dissociated control of these three human HSC bio-responses, and set the stage for future improvements in strategies to modify and expand human HSCs ex vivo. [Display omitted] •Growth factors alone can maintain serially transplantable human cord blood HSCs•Growth factors tunably and combinatorially control HSC survival and proliferation•SCF is a critical factor for stimulating human HSC proliferation•HSC regenerative activity is regulated independent of HSC survival or proliferation Eaves and colleagues show five growth factors alone can maintain transplantable human hematopoietic stem cell (HSC) activity for 21 days in vitro, through many divisions and the production of thousands of differentiating progeny. Single-cell tracking showed HSC survival and proliferation are regulated in a combinatorial and tunable manner, with SCF most potently stimulating HSC proliferation, multiple single growth factors promoting survival, and the regenerative activity of HSCs regulated independently of either their proliferation or survival.