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The Early Phase of Engraftment After Murine Blood Cell Transplantation Is Mediated by Hematopoietic Stem Cells

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The Early Phase of Engraftment After Murine Blood Cell Transplantation Is Mediated by Hematopoietic Stem Cells Proc. Natl. Acad. Sci. USA Vol. 95, pp. 725–729, January 1998 Medical Sciences The early phase of engraftment after murine blood cell transplantation is mediated by hematopoietic stem cells J. MARK J. M. ZIJLMANS*†‡,JAN W. M. VISSER§,LAURENS LATERVEER*, KARIN KLEIVERDA¶, DIANA P. M. HEEMSKERK*, PHILIP M. KLUIN¶,ROEL WILLEMZE*, AND WILLEM E. FIBBE* *Laboratory of Experimental Hematology, Department of Hematology, and ¶Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; and §Lindsley F. Kimball Research Institute, Laboratory of Stem Cell Biology, New York Blood Center, New York, NY 10021 Communicated by Johannes van Rood, Leiden University, Leiden, Netherlands, November 4, 1997 (received for review June 9, 1997) ABSTRACT Blood cell transplantation is largely replac- these arguments do not provide formal proof for the concept, ing bone marrow transplantation because engraftment is large-scale ex vivo expansion of committed progenitor cells is more rapid. This accelerated engraftment is thought to be being developed with the aim to further enhance engraftment mediated by relatively mature committed hematopoietic pro- (8, 13–16). genitor cells. Herein, we have used a modified rhodamine To identify the cell population mediating the early phase of (Rho) staining procedure to identify and purify Rho1/11 hematopoietic reconstitution after blood cell transplantation, (dullybright) and Rho2 (negative) subpopulations of hema- we have used a recently developed method to purify subpopu- topoietic progenitor cells in murine cytokine-mobilized blood. lations of murine hematopoietic progenitor cells (17). Herein, 1 11 The Rho / cell population contained >99% of committed we identified purified populations of immature stem cells or 2 progenitor cells with in vitro colony-forming ability. The Rho committed progenitor cells in murine cytokine-mobilized cell population contained the majority of hematopoietic stem blood. Engraftment was accelerated by transplanting higher cells with in vivo marrow repopulating ability. The rate of numbers of stem cells and not by adding large numbers of hematopoietic reconstitution was identical in recipients of committed progenitor cells. In cotransplantation experiments, 2 grafts containing only purified Rho stem cells or purified a severely reduced long-term repopulating ability (LTRA) of 2 Rho stem cells in combination with large numbers of mobilized blood cells in comparison to bone marrow cells was 1 11 Rho / committed progenitor cells. In contrast, transplan- observed. We conclude that stem cells and not committed tation of 3-fold more hematopoietic stem cells resulted in progenitor cells mediate the early phase of engraftment after accelerated reconstitution, indicating that the reconstitution blood cell transplantation and that the rate of engraftment is 2 rate was determined by the absolute numbers of Rho stem determined by the absolute number of stem cells in the graft. cells in the graft. In addition, we observed a 5- to 8-fold reduced frequency of the subset of hematopoietic stem cells with long-term repopulating ability in cytokine-mobilized MATERIALS AND METHODS blood in comparison to steady-state bone marrow. Our results Stem Cell Mobilization. Male BALByc donor mice (Broekman indicate that hematopoietic stem cells and not committed B.V., Someren, The Netherlands), ranging from 8 to 12 weeks of progenitor cells mediate early hematopoietic reconstitution age, were treated with cyclophosphamide at 400 mgykg i.p. on day after blood cell transplantation and that relative to bone 0 and 5 mg of human granulocyte colony-stimulating factor marrow, the frequency of stem cells with long-term repopu- (Amgen Biologicals) per mouse daily s.c. on days 1–5. On day 5, lating ability is reduced in mobilized blood. mice were killed by CO2 asphyxia. Blood was harvested by cardiac puncture and collected in heparin-containing tubes. Steady-state Mature blood cells are produced by hematopoietic progenitor bone marrow cells were harvested from the femurs of untreated cells in the bone marrow. Within this progenitor cell popula- animals. The protocol was approved by the institutional commit- tion, relatively immature stem cells and more mature commit- tee on animal experiments. ted progenitor cells can be distinguished (for reviews, see refs. Purification of Subpopulations of Progenitor Cells. All wash- 1 and 2). After myelo-ablative treatment and bone marrow ing, incubation, and purification procedures were done in RPMI transplantation, mature blood cell production (i.e., engraft- 1640 medium supplemented with 2% fetal bovine serum, peni- ment) is resumed after an interval of 2–3 weeks (3). Engraft- cillin (500 mgyml), and streptomycin (250 mgyml) (GIBCOy ment is thought to be mediated initially by committed pro- BRL). Low-density cells (FicollyIsopaque; 1.077 gycm3), derived genitor cells and finally by stem cells. Several arguments from mobilized blood or steady-state bone marrow, were labeled support this concept. (i) Multiple cell divisions and maturation with mAb 15-1.1 (Rat IgG2b), binding to cells from myelo- steps separate the most immature stem cells from mature monocytic lineages (Lin) (17). Cells were washed and incubated blood cells (1). Less-immature committed progenitor cells may with fluorescein isothiocyanate-conjugated wheat germ aggluti- require fewer cell divisions to produce mature blood cells. (ii) nin (WGA, 0.2 mgyml, Vector Laboratories) and phycoerythrin- Several murine in vivo studies using different cell separation conjugated goat anti-Rat IgG (Caltag, South San Francisco, CA). methods showed that early engraftment is mediated by cell WGA1yLin2 cells (representing 18 6 6% and 5 6 2% in blood populations that were relatively enriched for committed pro- and bone marrow, respectively) were sorted by using a FACStar genitors (4–9). (iii) Cytokine-mobilized blood cell grafts con- flow cytometer (Becton Dickinson) equipped with a 5-W argon tain increased numbers of committed progenitor cells com- laser tuned at 488 nm (0.2 W). Sorted WGA1yLin2 cells were pared with bone marrow grafts, and transplantation of these grafts results in an earlier engraftment (10–12). Although Abbreviations: LTRA, long-term repopulating ability; STRA, short- term repopulating ability; Rho, rhodamine; VP, verapamil; CFC, The publication costs of this article were defrayed in part by page charge colony-forming cell; WGA, wheat germ agglutinin. †Present address: Institute of Hematology, Erasmus University Rot- payment. This article must therefore be hereby marked ‘‘advertisement’’ in terdam, 3000 DR Rotterdam, The Netherlands. accordance with 18 U.S.C. §1734 solely to indicate this fact. ‡To whom reprint requests should be addressed at: Institute of © 1998 by The National Academy of Sciences 0027-8424y98y95725-5$2.00y0 Hematology, Erasmus University Rotterdam, P.O. Box 1738, 3000 PNAS is available online at http:yywww.pnas.org. DR Rotterdam, The Netherlands. 725 Downloaded by guest on October 3, 2021 726 Medical Sciences: Zijlmans et al. Proc. Natl. Acad. Sci. USA 95 (1998) stained with rhodamine-123 (Rho, Molecular Probes) at a con- RESULTS centration of 0.1 mgyml (20 min, 37°C), washed twice (20°C), and Identification of Purified Populations of Stem Cells and then incubated in Rho-free medium (20 min, 37°C). Rho fluo- Committed Progenitor Cells in Cytokine-Mobilized Blood. rescence was measured by using excitation and emission wave Stem cell mobilization was induced by treating donor mice with lengths of 514 and 580 nm, respectively (17). In some experi- 1 2 2 cyclophosphamide and granulocyte colony-stimulating factor. ments, sorted WGA yLin yRho cells were subjected to a To purify cell fractions containing either stem cells or com- second Rho staining procedure with the use of verapamil (VP) 1 2 mitted progenitor cells, WGA yLin cells were sorted and (17). After restaining with Rho (0.1 mgyml, 20 min, 37°C) and subjected to a modified Rho staining procedure resulting in washing twice (4°C), the cells were incubated in medium without 11 1 distinct populations of Rho (bright), Rho (dull), and Rho (20 min, 37°C) in the presence of VP (10 mM). Distinct 2 1 2 Rho (negative) cells (Fig. 1A). In comparison with steady- populations of Rho(VP) and Rho(VP) cells could be identi- 1 2 state bone marrow, WGA yLin cells derived from mobilized fied. blood contained more Rho11 cells and fewer Rho1 and Rho2 Characterization of Committed Progenitor Cells. A total of 1y 2y 2 1y 2y 1/11 cells. Committed progenitor cells, defined by their in vitro 200–750 WGA Lin Rho or WGA Lin Rho responsiveness to a combination of hematopoietic growth sorted cells from blood or bone marrow were cultured in factors, resided in the Rho1/11 fractions of WGA1yLin2 cells 35-mm tissue culture dishes in Iscove’s modified Dulbecco’s for .99% (Table 1). After transplantation into lethally irra- medium, containing 30% fetal calf serum, 1% deionized BSA, diated recipients, these committed progenitor cell populations 2 3 1025 M 2-mercaptoethanol, human transferrin (0.47 y z had a poor radioprotective capacity because 50% survival g liter) saturated with FeCl3 H2O and 1.1% methylcellulose in required transplantation of 3,000 Rho1 cells or .20,000 the presence of hematopoietic growth factors, i.e., murine Rho11 cells (Fig. 1B). In contrast, 50% survival was observed granulocyte–macrophage colony-stimulating factor (10 ngy ml) and murine interleukin 3 (25 ngyml), both provided by I. Lindley, Sandoz, Basel, Switzerland; human granulocyte col- ony-stimulating factor (10 ngyml) and human erythropoietin (2 unitsyml; Organon Technica, Turnhout, Belgium). Colonies were counted on day 12 of culture. Characterization of Hematopoietic Stem Cells. BALByc recipient mice (8–12 weeks of age) were given total body irradiation of 8.5 Gy divided in two equal parts in posterior– anterior and anterior–posterior position, at a dose of 4 Gyymin with a Philips SL 75-5y6 mV linear accelerator (Philips Medical Systems, Best, The Netherlands). All control mice (n 5 21), not transplanted with donor cells, died between 12 and 18 days after irradiation.
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