Heterogeneity and Hierarchy Within the Most Primitive Hematopoietic Stem Cell Compartment

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2010 Apr 28

PMID 20421392

Citations 221

Authors

Yohei Morita

Hideo Ema

Hiromitsu Nakauchi

Affiliations

Soon will be listed here.

Abstract

Hematopoietic stem cells (HSCs) have been extensively characterized based on functional definitions determined by experimental transplantation into lethally irradiated mice. In mice, HSCs are heterogeneous with regard to self-renewal potential, in vitro colony-forming activity, and in vivo behavior. We attempted prospective isolation of HSC subsets with distinct properties among CD34(-/low) c-Kit+Sca-1+Lin- (CD34-KSL) cells. CD34-KSL cells were divided, based on CD150 expression, into three fractions: CD150high, CD150med, and CD150neg cells. Compared with the other two fractions, CD150high cells were significantly enriched in HSCs, with great self-renewal potential. In vitro colony assays revealed that decreased expression of CD150 was associated with reduced erythroblast/megakaryocyte differentiation potential. All three fractions were regenerated only from CD150high cells in recipient mice. Using single-cell transplantation studies, we found that a fraction of CD150high cells displayed latent and barely detectable myeloid engraftment in primary-recipient mice but progressive and multilineage reconstitution in secondary-recipient mice. These findings highlight the complexity and hierarchy of reconstitution capability, even among HSCs in the most primitive compartment.

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References

Arinobu Y, Mizuno S, Chong Y, Shigematsu H, Iino T, Iwasaki H . Reciprocal activation of GATA-1 and PU.1 marks initial specification of hematopoietic stem cells into myeloerythroid and myelolymphoid lineages. Cell Stem Cell. 2008; 1(4):416-27. DOI: 10.1016/j.stem.2007.07.004. View

Kiel M, Yilmaz O, Iwashita T, Yilmaz O, Terhorst C, Morrison S . SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005; 121(7):1109-21. DOI: 10.1016/j.cell.2005.05.026. View

Dykstra B, Kent D, Bowie M, McCaffrey L, Hamilton M, Lyons K . Long-term propagation of distinct hematopoietic differentiation programs in vivo. Cell Stem Cell. 2008; 1(2):218-29. DOI: 10.1016/j.stem.2007.05.015. View

Yamazaki S, Iwama A, Takayanagi S, Eto K, Ema H, Nakauchi H . TGF-beta as a candidate bone marrow niche signal to induce hematopoietic stem cell hibernation. Blood. 2008; 113(6):1250-6. DOI: 10.1182/blood-2008-04-146480. View

Zhang J, Niu C, Ye L, Huang H, He X, Tong W . Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003; 425(6960):836-41. DOI: 10.1038/nature02041. View

Kent D, Copley M, Benz C, Wohrer S, Dykstra B, Ma E . Prospective isolation and molecular characterization of hematopoietic stem cells with durable self-renewal potential. Blood. 2009; 113(25):6342-50. DOI: 10.1182/blood-2008-12-192054. View

Balazs A, Fabian A, Esmon C, Mulligan R . Endothelial protein C receptor (CD201) explicitly identifies hematopoietic stem cells in murine bone marrow. Blood. 2005; 107(6):2317-21. PMC: 1895725. DOI: 10.1182/blood-2005-06-2249. View

Kiel M, Radice G, Morrison S . Lack of evidence that hematopoietic stem cells depend on N-cadherin-mediated adhesion to osteoblasts for their maintenance. Cell Stem Cell. 2008; 1(2):204-17. DOI: 10.1016/j.stem.2007.06.001. View

Sieburg H, Cho R, Dykstra B, Uchida N, Eaves C, Muller-Sieburg C . The hematopoietic stem compartment consists of a limited number of discrete stem cell subsets. Blood. 2005; 107(6):2311-6. PMC: 1456063. DOI: 10.1182/blood-2005-07-2970. View

10.

Yoshihara H, Arai F, Hosokawa K, Hagiwara T, Takubo K, Nakamura Y . Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell. 2008; 1(6):685-97. DOI: 10.1016/j.stem.2007.10.020. View

11.

Yamazaki S, Iwama A, Takayanagi S, Morita Y, Eto K, Ema H . Cytokine signals modulated via lipid rafts mimic niche signals and induce hibernation in hematopoietic stem cells. EMBO J. 2006; 25(15):3515-23. PMC: 1538571. DOI: 10.1038/sj.emboj.7601236. View

12.

Ema H, Morita Y, Yamazaki S, Matsubara A, Seita J, Tadokoro Y . Adult mouse hematopoietic stem cells: purification and single-cell assays. Nat Protoc. 2007; 1(6):2979-87. DOI: 10.1038/nprot.2006.447. View

13.

Kiel M, Acar M, Radice G, Morrison S . Hematopoietic stem cells do not depend on N-cadherin to regulate their maintenance. Cell Stem Cell. 2009; 4(2):170-9. PMC: 2681089. DOI: 10.1016/j.stem.2008.10.005. View

14.

Ema H, Takano H, Sudo K, Nakauchi H . In vitro self-renewal division of hematopoietic stem cells. J Exp Med. 2000; 192(9):1281-8. PMC: 2193353. DOI: 10.1084/jem.192.9.1281. View

15.

Adolfsson J, Borge O, Bryder D, Theilgaard-Monch K, Sitnicka E, Sasaki Y . Upregulation of Flt3 expression within the bone marrow Lin(-)Sca1(+)c-kit(+) stem cell compartment is accompanied by loss of self-renewal capacity. Immunity. 2001; 15(4):659-69. DOI: 10.1016/s1074-7613(01)00220-5. View

16.

Foudi A, Hochedlinger K, Van Buren D, Schindler J, Jaenisch R, Carey V . Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells. Nat Biotechnol. 2008; 27(1):84-90. PMC: 2805441. DOI: 10.1038/nbt.1517. View

17.

Adolfsson J, Mansson R, Buza-Vidas N, Hultquist A, Liuba K, Jensen C . Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential a revised road map for adult blood lineage commitment. Cell. 2005; 121(2):295-306. DOI: 10.1016/j.cell.2005.02.013. View

18.

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

19.

Sudo K, Ema H, Morita Y, Nakauchi H . Age-associated characteristics of murine hematopoietic stem cells. J Exp Med. 2000; 192(9):1273-80. PMC: 2193349. DOI: 10.1084/jem.192.9.1273. View

20.

Ema H, Sudo K, Seita J, Matsubara A, Morita Y, Osawa M . Quantification of self-renewal capacity in single hematopoietic stem cells from normal and Lnk-deficient mice. Dev Cell. 2005; 8(6):907-14. DOI: 10.1016/j.devcel.2005.03.019. View