Hematopoietic Stem Cells Count and Remember Self-Renewal Divisions

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2016 Nov 15

PMID 27839867

Citations 142

Authors

Jeffrey M Bernitz

Huen Suk Kim

Ben MacArthur

Hans Sieburg

Kateri Moore

Affiliations

Soon will be listed here.

Abstract

The ability of cells to count and remember their divisions could underlie many alterations that occur during development, aging, and disease. We tracked the cumulative divisional history of slow-cycling hematopoietic stem cells (HSCs) throughout adult life. This revealed a fraction of rarely dividing HSCs that contained all the long-term HSC (LT-HSC) activity within the aging HSC compartment. During adult life, this population asynchronously completes four traceable symmetric self-renewal divisions to expand its size before entering a state of dormancy. We show that the mechanism of expansion involves progressively lengthening periods between cell divisions, with long-term regenerative potential lost upon a fifth division. Our data also show that age-related phenotypic changes within the HSC compartment are divisional history dependent. These results suggest that HSCs accumulate discrete memory stages over their divisional history and provide evidence for the role of cellular memory in HSC aging.

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References

Majumdar A, Cesario W, White-Grindley E, Jiang H, Ren F, Khan M . Critical role of amyloid-like oligomers of Drosophila Orb2 in the persistence of memory. Cell. 2012; 148(3):515-29. DOI: 10.1016/j.cell.2012.01.004. View

Benz C, Copley M, Kent D, Wohrer S, Cortes A, Aghaeepour N . Hematopoietic stem cell subtypes expand differentially during development and display distinct lymphopoietic programs. Cell Stem Cell. 2012; 10(3):273-83. DOI: 10.1016/j.stem.2012.02.007. View

Dykstra B, Olthof S, Schreuder J, Ritsema M, de Haan G . Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells. J Exp Med. 2011; 208(13):2691-703. PMC: 3244040. DOI: 10.1084/jem.20111490. View

Si K, Giustetto M, Etkin A, Hsu R, Janisiewicz A, Miniaci M . A neuronal isoform of CPEB regulates local protein synthesis and stabilizes synapse-specific long-term facilitation in aplysia. Cell. 2003; 115(7):893-904. DOI: 10.1016/s0092-8674(03)01021-3. View

Levine J, Fontes M, Dworkin J, Elowitz M . Pulsed feedback defers cellular differentiation. PLoS Biol. 2012; 10(1):e1001252. PMC: 3269414. DOI: 10.1371/journal.pbio.1001252. View

Muller-Sieburg C, Cho R, Thoman M, Adkins B, Sieburg H . Deterministic regulation of hematopoietic stem cell self-renewal and differentiation. Blood. 2002; 100(4):1302-9. View

MacLennan I, Gray D . Antigen-driven selection of virgin and memory B cells. Immunol Rev. 1986; 91:61-85. DOI: 10.1111/j.1600-065x.1986.tb01484.x. View

Harley C, Futcher A, Greider C . Telomeres shorten during ageing of human fibroblasts. Nature. 1990; 345(6274):458-60. DOI: 10.1038/345458a0. View

Mohrin M, Bourke E, Alexander D, Warr M, Barry-Holson K, Le Beau M . Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell. 2010; 7(2):174-85. PMC: 2924905. DOI: 10.1016/j.stem.2010.06.014. View

10.

Qiu J, Papatsenko D, Niu X, Schaniel C, Moore K . Divisional history and hematopoietic stem cell function during homeostasis. Stem Cell Reports. 2014; 2(4):473-90. PMC: 3986626. DOI: 10.1016/j.stemcr.2014.01.016. View

11.

Insco M, Leon A, Tam C, McKearin D, Fuller M . Accumulation of a differentiation regulator specifies transit amplifying division number in an adult stem cell lineage. Proc Natl Acad Sci U S A. 2009; 106(52):22311-6. PMC: 2799733. DOI: 10.1073/pnas.0912454106. View

12.

Cho R, Sieburg H, Muller-Sieburg C . A new mechanism for the aging of hematopoietic stem cells: aging changes the clonal composition of the stem cell compartment but not individual stem cells. Blood. 2008; 111(12):5553-61. PMC: 2424153. DOI: 10.1182/blood-2007-11-123547. View

13.

Wilson A, Laurenti E, Oser G, van der Wath R, Blanco-Bose W, Jaworski M . Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell. 2008; 135(6):1118-29. DOI: 10.1016/j.cell.2008.10.048. View

14.

Haas S, Hansson J, Klimmeck D, Loeffler D, Velten L, Uckelmann H . Inflammation-Induced Emergency Megakaryopoiesis Driven by Hematopoietic Stem Cell-like Megakaryocyte Progenitors. Cell Stem Cell. 2015; 17(4):422-34. DOI: 10.1016/j.stem.2015.07.007. View

15.

Muller-Sieburg C, Cho R, Karlsson L, Huang J, Sieburg H . Myeloid-biased hematopoietic stem cells have extensive self-renewal capacity but generate diminished lymphoid progeny with impaired IL-7 responsiveness. Blood. 2004; 103(11):4111-8. DOI: 10.1182/blood-2003-10-3448. View

16.

Nakamura-Ishizu A, Takizawa H, Suda T . The analysis, roles and regulation of quiescence in hematopoietic stem cells. Development. 2014; 141(24):4656-66. DOI: 10.1242/dev.106575. View

17.

Beerman I, Seita J, Inlay M, Weissman I, Rossi D . Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell. 2014; 15(1):37-50. PMC: 4082747. DOI: 10.1016/j.stem.2014.04.016. View

18.

Essers M, Offner S, Blanco-Bose W, Waibler Z, Kalinke U, Duchosal M . IFNalpha activates dormant haematopoietic stem cells in vivo. Nature. 2009; 458(7240):904-8. DOI: 10.1038/nature07815. View

19.

Busch K, Klapproth K, Barile M, Flossdorf M, Holland-Letz T, Schlenner S . Fundamental properties of unperturbed haematopoiesis from stem cells in vivo. Nature. 2015; 518(7540):542-6. DOI: 10.1038/nature14242. View

20.

Rossi D, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman I . Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature. 2007; 447(7145):725-9. DOI: 10.1038/nature05862. View