Highly potent human hematopoietic stem cells first emerge in the intraembryonic aorta-gonad-mesonephros region - PubMed (original) (raw)
Highly potent human hematopoietic stem cells first emerge in the intraembryonic aorta-gonad-mesonephros region
Andrejs Ivanovs et al. J Exp Med. 2011.
Abstract
Hematopoietic stem cells (HSCs) emerge during embryogenesis and maintain hematopoiesis in the adult organism. Little is known about the embryonic development of human HSCs. We demonstrate that human HSCs emerge first in the aorta-gonad-mesonephros (AGM) region, specifically in the dorsal aorta, and only later appear in the yolk sac, liver, and placenta. AGM region cells transplanted into immunodeficient mice provide long-term high level multilineage hematopoietic repopulation. Human AGM region HSCs, although present in low numbers, exhibit a very high self-renewal potential. A single HSC derived from the AGM region generates at least 300 daughter HSCs in primary recipients, which disseminate throughout the entire recipient bone marrow and are retransplantable. These findings highlight the vast regenerative potential of the earliest human HSCs and set a new standard for in vitro generation of HSCs from pluripotent stem cells for the purpose of regenerative medicine.
Figures
Figure 1.
Human AGM region-derived HSCs provide progressive growth of hematopoietic contribution in NSG mice. (A) Representative flow cytometry plots show hematopoietic cells in the peripheral blood and BM of an NSG mouse transplanted with 0.33 e.e. of AGM region cells. In this case, the AGM region was obtained from a CS 16 embryo. The repopulation kinetics was monitored for 8 mo. hCD45, human CD45. (B) Human hematopoietic engraftment kinetics in the peripheral blood of 10 NSG recipient mice transplanted with human AGM region or yolk sac cells. The numbers at the end of the time series correspond to the recipient identification numbers in Table II.
Figure 2.
Human AGM region–derived HSCs provide long-term multilineage hematopoietic engraftment. Representative flow cytometry plots show human B cells (A), T cells (B and C), NK and NKT cells (D), granulocytes and monocytes (E), platelets (F), and erythroid cells (G) in the peripheral blood, BM, spleen, and/or thymus of an NSG mouse 7 mo after it was transplanted with 0.5 e.e. of AGM region cells. In this case, the AGM region was obtained from a CS 17 embryo. Note that the staining for CD4 and CD8 is shown in gated human CD45+ cells, and for TCRs in gated human CD3+ cells. Plating BM of the same recipient into methylcellulose medium supplemented with human cytokines resulted in the formation of human erythroid colonies (BFU-Es; H) and mixed erythromyeloid colonies (CFU-Mix; I). Bars, 0.5 mm.
Figure 3.
Human AGM region-derived HSCs provide long-term multilineage hematopoietic engraftment upon retransplantation into secondary recipients. Representative flow cytometry plots show human B (CD19+), T (CD3+), and myeloid cells (CD33+) in the peripheral blood (A) and BM (B) of an NSG mouse transplanted with BM from a primary recipient engrafted with HSCs from a CS 15 AGM region. Secondary transplantation was performed 7 mo after primary transplantation. The analysis of secondary recipients was performed 7 mo later. Eight independent secondary transplantation experiments were performed.
Figure 4.
Extensive amplification of human AGM region–derived HSCs in primary recipients. (A) Results of 10 independent experiments in which HSCs were detected in AGM regions are plotted as the natural logarithm of the fraction of nonengrafted mice versus the dose of donor tissues (e.e. per recipient) transplanted in each experiment. The solid line shows the mean value. The dotted lines indicate 95% confidence interval. The data value with zero negative response (two out of two recipients were found engrafted with human HSCs) is represented by a down-pointing triangle. (B and C) 8 mo after transplantation, BM (B) and spleen (C) from a primary recipient repopulated with a single HSC from the AGM region of a CS 16 embryo were harvested and transplanted into secondary recipients (two independent experiments). Peripheral blood of secondary recipients was analyzed for human CD45+ cell contribution 2 mo after transplantation. The ratios below the charts indicate the fraction of total BM or spleen transplanted per recipient.
Figure 5.
Extensive recipient BM colonization by daughter HSCs generated from a single AGM region-derived HSC. (A) AGM region cells obtained from a CS 15 embryo were transplanted into three NSG mice (0.33 e.e. per recipient). Only one of the three recipients showed human hematopoietic repopulation (mouse c). We confirmed by secondary transplantation that the other two recipients (mice a and b) contained no activatable HSCs. To test if the single human HSC that repopulated mouse c had generated daughter HSCs which could spread across the recipient BM, BM cells from two coxal bones, two femurs, and two tibiae were harvested and separately transplanted into six secondary recipients (mice 1–6). Secondary transplantations were performed 4 mo after the primary transplantation. (B) Representative flow cytometry plots show human hematopoietic repopulation in the peripheral blood of the six secondary recipients 3 mo later. Two independent experiments were performed. mCD45, mouse CD45.
Figure 6.
Daughter human AGM region-derived HSCs in primary recipients are CD34+CD38−/lo. (A) 7 mo after primary transplantation, BM of NSG mice repopulated with CS 16 and 17 AGM regions was sorted into four cell populations based on expression of human CD34 and CD38 antigens (two independent experiments). (B) Cells of each sorted population were injected into secondary recipients as indicated, and peripheral blood was analyzed 2 mo later. Two independent experiments were performed. K, multiple of thousand; M, multiple of million.
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