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New Evidence Supporting Megakaryocyte- Erythrocyte Potential of Flk2/Flt3+ Multipotent Hematopoietic Progenitors

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New Evidence Supporting Megakaryocyte- Erythrocyte Potential of Flk2/Flt3+ Multipotent Hematopoietic Progenitors View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Matters Arising New Evidence Supporting Megakaryocyte- Erythrocyte Potential of Flk2/Flt3+ Multipotent Hematopoietic Progenitors E. Camilla Forsberg,1,3,* Thomas Serwold,1 Scott Kogan,2 Irving L. Weissman,1 and Emmanuelle Passegue´ 1,3,4,* 1 Institute of Stem Cell Biology and Regenerative Medicine, Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA 2 Department of Laboratory Medicine and Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA 3 These authors contributed equally to this work. 4 Present Address: Developmental and Stem Cell Biology Program, University of California, San Francisco, CA 94143, USA. *Contact: [email protected] (E.C.F.); [email protected] (E.P.) DOI 10.1016/j.cell.2006.06.037 SUMMARY model states that only the most primitive long-term recon- stituting subset of HSC (LT-HSC) self-renew for life and A model of hematopoietic development wherein give rise to short-term reconstituting subsets of HSC multipotentiality is conserved until segregation (ST-HSC), with limited self-renewal activity, and then to of myeloid and lymphoid potential has recently multipotent progenitors (MPP) that do not self-renew been challenged, proposing that megakaryo- (Spangrude et al., 1988; Morrison et al., 1997; Christensen cyte/erythrocyte (MegE) potential is lost in and Weissman, 2001). In this model, differentiation prog- Flk2/Flt3-expressing early progenitors. Here, resses with segregation of myeloid and lymphoid lineages through the generation of common myeloid progenitors we used sensitive in vivo approaches to quanti- (CMP) (Akashi et al., 2000) and common lymphoid progen- tatively and kinetically assess the MegE poten- itors (CLP) (Kondo et al., 1997). Both CLP and CMP un- tial of hematopoietic stem cells and various dergo further lineage segregation, with CMP giving rise + Flk2 early progenitors and compared it with to myelomonocytic progenitors (GMP) and megakaryo- the MegE potential of downstream committed cyte/erythrocyte progenitors (MEP) that separate granulo- myeloid and lymphoid progenitors and with cyte and macrophage production from red blood cell and their ability to give rise to mature myelomono- platelet production (Akashi et al., 2000). cytic and lymphoid cells. We demonstrate that In the mouse, multipotent hematopoietic activity is con- Flk2+ early progenitors retain MegE potential in tained in a small fraction of the bone marrow that lacks vivo both at the population and clonal levels. expression of mature hematolymphoid-associated cell- These results indicate that Flk2 expression by surface markers (lineage or ‘‘Lin’’ markers) and displays high levels of the stem cell-associated markers c-Kit and early progenitors is not at the expense of full Sca-1 (LinÀ/c-Kit+/Sca-1+ or ‘‘KLS’’) (Spangrude et al., multipotency and support the current model of 1988; Ikuta and Weissman, 1992). The KLS fraction can hematopoietic development with segregation be further subdivided into functionally distinct subpopula- of myeloid and lymphoid lineages from multi- tions based on the expression levels of the Thy1.1 potent progenitors. (Spangrude et al., 1988), CD4 and Mac-1 (Morrison and Weissman, 1994), CD34 (Osawa et al., 1996), Flk2/Flt3 INTRODUCTION (Adolfsson et al., 2001; Christensen and Weissman, 2001), and the Slam family (Kiel et al., 2005; Forsberg Hematopoietic development is one of the most intensely et al., 2005) of surface molecules. Within the KLS fraction, studied systems of cellular differentiation, where multipo- loss of Thy1.1 and gain of Flk2 expression correlates with tent self-renewing hematopoietic stem cells (HSC) give decreased self-renewal ability (Adolfsson et al., 2001; rise to a hierarchy of progenitor populations with more Christensen and Weissman, 2001) and increased proli- restricted lineage potential, ultimately leading to the pro- feration (Passegue´ et al., 2005). Recently, it has been duction of all types of mature blood cells. Prospective reported that Flk2-expressing KLS cells might not be isolation of cellular subsets based on expression of cell- fully multipotent because they failed to generate signifi- surface markers followed by functional characterization cant megakaryocyte (Meg) and erythrocyte (E) progenies using in vitro and in vivo assays has provided key insights in the assays used in those studies (Yang et al., 2005; into hematopoietic development (Weissman, 2000). One Adolfsson et al., 2005). Conclusions from those reports Cell 126, 415–426, July 28, 2006 ª2006 Elsevier Inc. 415 challenged the current fate map of hematopoietic devel- RESULTS opment and the existence of MPP and CMP populations by suggesting that early progenitor populations might se- Tracking the Lineage Potential of Stem quentially lose lineage potential as they differentiate from and Progenitor Cells LT-HSC, starting with loss of MegE potential (Adolfsson Due to differences in self-renewal ability and proliferation et al., 2005; also see commentaries by Akashi et al., rates, stem and progenitor cells differ considerably in their 2005; Hock and Orkin, 2005). ability to expand both in vitro and in vivo. To assay the An important test for HSC function is their ability to expansion capacity of LT-HSC, ST-HSCF, MPPF, CMP, reconstitute the blood system of an irradiated host, includ- GMP, and MEP in vitro, cells were grown in liquid media ing the HSC pool. Commonly, donor cells are distin- containing cytokines and growth factors promoting mye- guished from host cells by transplantation of purified pop- loerythroid proliferation and differentiation (Figure 1A). ulations into conditioned hosts with an allelic difference in For the first 4 days of culture, MPPF displayed the greatest the hematopoietic cell-surface marker CD45, followed by rate of expansion, while by days 6 and 8 ST-HSCF and allele-specific antibody labeling (Spangrude et al., 1988). LT-HSC, respectively, accumulated to a larger extent. While all mature myelomonocytic and lymphoid cells ex- Among the myeloid progenitors, CMP displayed a kinetics press robust CD45 levels, mature cells of the MegE line- of expansion very similar to MPPF, while GMP and MEP age lack CD45 expression, making it difficult to assess proliferated poorly throughout the culture period. After directly whether the transplanted cells are capable of 8 days, LT-HSC had undergone an expansion of 1600- forming platelets and red blood cells in vivo. Furthermore, fold, ST-HSCF of 1200-fold, MPPF of 350-fold, CMP while single-cell assessment of lineage potential is feasi- of 250-fold, MEP of 81-fold, and GMP of 65-fold. ble for LT-HSC (Smith et al., 1991; Wagers et al., 2002; These results indicate an inverse correlation between Osawa et al., 1996; Adolfsson et al., 2001), progenitors the burst size of each progenitor population and its degree with lower self-renewal potential give rise to insufficient of maturation, which has to be taken into account when numbers of progeny for robust single-cell detection investigating lineage potential in vivo. The differentiation in vivo. Thus, as self-renewal ability declines, increasing potential of each population was also investigated at the numbers of input cells are needed to allow detection of single-cell level in methylcellulose media and further con- progeny. In addition, mature myeloid cells are short lived firmed the direct correlation between the time course of (days), while a significant fraction of mature lymphocytes differentiation and the developmental stage of the starting are long lived (months to years), enabling easier detection population (Figure S1). of lymphoid versus myeloerythroid progeny at late time To circumvent the lack of CD45 expression by mature points. Together, these limitations have made it difficult to cells of the MegE lineage, we used b-actin GFP transgenic assess in vivo the full lineage potential of early progenitor mice (Wright et al., 2001) as a source of donor cells and cells. transplanted purified stem and progenitor populations at Here, we have used sensitive in vivo approaches to various doses into sublethally irradiated (475 rad) con- quantitatively and kinetically assay the MegE potential genic wild-type recipient mice (Figure 1B). For all experi- of the KLS fraction of mouse bone marrow, divided ments cells were double or triple sorted to ensure into LT-HSC (Thy1.1int/Flk2À KLS), short-term HSC maximum purity. Since all platelets (Plt) (Nakorn et al., (ST-HSCF: Thy1.1int/Flk2+ KLS), multipotent progenitor 2003) and nucleated myelomonocytic and lymphoid cells population (MPPF: Thy1.1À/Flk2+ KLS) (Christensen and in the peripheral blood (PB) of b-actin GFP mice are Weissman, 2001), or ‘‘lymphoid-primed’’ multipotent pro- positive for GFP (Figures 1C and 1D), this assay enabled genitors (LMPP: 25% brightest Flk2+ KLS) (Adolfsson direct and quantitative in vivo tracking of mature cell pro- et al., 2005), and compared it with the MegE potential of duction by each transplanted population. The use of sub- downstream myeloid (CMP, GMP, and MEP) and lym- lethal irradiation, as opposed to lethal irradiation, allowed phoid (CLP) progenitors and with their ability to give rise us to follow the kinetics of mature cell production with to mature myelomonocytic and lymphoid cells in vivo. high resolution, starting within days after transplantation. We demonstrate that Flk2+ ST-HSCF, MPPF, and LMPP retain MegE potential at the population and clonal levels Platelet Production in vivo, readily detectable when sufficient numbers of To determine whether Flk2 expression identifies a KLS input cells are provided and when progeny are investi- population lacking MegE potential, we purified in parallel gated at the early and late time points. We also estab- LT-HSC, ST-HSCF, MPPF (Christensen and Weissman, lished the timecourse of mature cell production by each 2001), and LMPP (Adolfsson et al., 2005) from b-actin of these progenitor populations, hence providing the tim- GFP mice (Figure 2A). The relationship between these ing required for these early differentiation events in vivo.
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