Journal
INTEGRATIVE BIOLOGY
Volume 1, Issue 1, Pages 59-69Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/b815718a
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Funding
- Swiss National Science Foundation
- Leukemia and Lymphoma Society
- Baxter Foundation
- NIH [AG009521, AG020961, AG024987]
- NATIONAL INSTITUTE ON AGING [R01AG009521, R37AG009521, R01AG020961, R01AG024987] Funding Source: NIH RePORTER
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Hematopoietic stem cells (HSCs) are capable of extensive self-renewal in vivo and are Successfully employed clinically to treat hematopoietic malignancies, yet are in limited Supply as in Culture this self-renewal capacity is lost. Using an approach at the interface of stem cell biology and bioengineering, here we describe a novel platform of hydrogel microwell arrays for assessing the effects of either secreted or tethered proteins characteristic of the in vivo microenvironment, or niche, on HSC fate in vitro. Time-lapse microscopic analyses of single cells were crucial to overcoming inevitable heterogeneity of FACS-enriched HSCs. A reduction in proliferation kinetics or an increase in asynchronous division of single HSCs in microwells in response to specific proteins (Wnt3a and N-Cadherin) correlated well with Subsequent serial long-term blood reconstitution in mice in vivo. Single cells that divided once in the presence of a given protein were capable of in vivo reconstitution, providing evidence of self-renewal divisions of HSCs in vitro. These results validate the hydrogel microwell platform as a broadly applicable paradigm for dissecting the regulatory role of specific signals within a complex stem cell niche.
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