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Regulation of developmental changes in hematopoietic stem cell self-renewal

University of British Columbia

Mouse hematopoietic stem cells (HSCs) undergo a post-natal transition in several properties, including a marked reduction in their self-renewal activity. To investigate the molecular basis of this difference, we devised a single strategy to isolate fetal and adult HSCs at similarly high frequencies. This strategy, involving fluorescence-activated cell sorting of cells with a CD45⁺EPCR⁺CD48-CD150⁺ (ESLAM) phenotype, allows isolation of HSCs at a frequency of ~1 in 2 from all developmental time points tested (mouse embryonic day (E) 14.5 to adult). Comparison of differentially expressed genes in primitive populations of fetal and adult hematopoietic cells showed that heightened expression of Hmga2 was a feature of fetal as compared to adult HSCs. We also identified let-7 microRNAs (miRNAs) and a negative regulator of their biogenesis, Lin28b, to be expressed in an opposite and similar pattern to Hmga2, respectively. Since Hmga2 is a well-established target of let-7 miRNAs, we hypothesized that the Lin28b-let-7-Hmga2 axis plays a central role in the determination of fetal versus adult HSC self-renewal identity. We also found that Lin28 overexpression in adult HSCs restores a higher, fetal-like, self-renewal potential in them, and this effect is phenocopied by direct overexpression of Hmga2. Conversely, HSCs from fetal Hmga2-/- mice display a prematurely acquired adult-like self-renewal activity. Importantly, we show that Lin28-mediated activation of Hmga2 expression, which is responsible for the activation of a fetal-like self-renewal potential in adult HSCs, is not the mechanism by which Lin28 reprograms adult HSCs to undergo fetal-like B-cell differentiation. Together, these findings suggest a model of development in which Lin28b acts as a master regulator and Hmga2 serves as a more specific downstream modulator of HSC self-renewal. These findings may help inform strategies to improve the therapeutic use of HSCs. Furthermore, since Lin28b and Hmga2 are oncogenes, we speculate that the fetal/neonatal specific pattern of expression of these genes may contribute to the pathogenesis of pediatric leukemias.

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2013-08-15

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/44819

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/