Although it has been reported previously that pluripotent hemopoietic stem cells (P-HSCs) express c-kit, the receptor for stem cell factor (steel factor), we and other groups have recently shown that P-HSCs do not express c-kit. In this review, we provide evidence that c-kit<low P-HSCs in mice have long-term-reconstituting activity (LTRA > 2 years) and the capacity to form colony-forming units in spleen (CFU-S) on Day 16, although c-kitlow HSCs or c-kit+ HSCs have LTRA less than 1.5 years and the capacity to form CFU-S on Day 14 or on Day 10, respectively. In addition, we have found that there is a major histocompatibility complex (MHC) restriction between P-HSCs and stromal cells; normal P-HSCs can proliferate and differentiate efficiently in collaboration with MHC class I-compatible (but not MHC class I-incompatible) stromal cells. In humans, we also show that c-kit<low P-HSCs can differentiate into c-kitlow cells, then c-kit+ cells in vitro.
Get full access to this article
View all access options for this article.
References
1.
WolfNS, KoneA, PriestleyGV, BartelmezSH. In vivo and in vitro characterization of long-term repopulating primitive hematopoietic stem cells isolated by sequential hoechst 33342-rhodamine 123 FACS selection. Exp Hematol21: 614622, 1993.
2.
SpangrudeGJ, BrooksDM, TumasDB. Long-term repopulation of irradiated mice with limited numbers of purified hematopoietic stem cells: In vivo expansion of stem cell phenotype but not function. Blood85: 10061016, 1995.
3.
SpangrudeGJ, BrooksDM. Mouse strain variability in the expression of the hematopoietic stem cell antigen Ly-6A/E by bone marrow cells. Blood82: 33273332, 1993.
4.
UchidaN, WeissmanIL. Searching for hematopoietic stem cells: Evidence that Thy-1.1lowLin-Sca-1+ cells are the only stem cells in C57BL/Ka-Thy-1.1 bone marrow. J Exp Med175: 175184, 1992.
5.
SpangrudeGJ, BrooksDM. Phenotype analysis of mouse hematopoietic stem cells shows a Thy-1-negative subset. Blood80: 19571964, 1992.
MorrisonSJ, WeissmanIL. The long-term hemopoietic repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity1: 661673, 1994.
8.
KrauseDS, ItoT, FacklerMJ, SmithOM, CollectorMI, SharkisSJ, MayWS. Characterization of murine CD34, a marker for hematopoietic progenitors and stem cells. Blood84: 691701, 1994.
9.
OrlicD, FischerR, NishikawaS-1, NienhuisAW, BodineDM. Purification and characterization of heterogeneous pluripoent hematopoietic stem cell populations expressing high levels of c-kit receptor. Blood2: 762770, 1993.
10.
IkutaK, WeissmanIL. Evidence that hematopoietic stem cells express c-kit, but do not depend on steel factor for their generation. Proc Natl Acad Sci U S A89: 15021506, 1992.
11.
OgawaM, MatsuzakiY, NishikawaS, HayashiS-I, KunisadaT, SudoT, KinaT, NakauchiH, NishikawaS-I. Expression and function of c-kit in hemopoietic progenitor cells. J Exp Med174: 6371, 1991.
12.
LiCL, JohnsonGR. Murine hematopoietic stem and progenitor cells: I. Enrichment and biologic characterization. Blood85: 14721479, 1995.
13.
TaniguchiH, ToyoshimaT, FukaoK, NakauchiH. Presence of hematopoietic stem cells in the adult liver. Nat Med2: 198203, 1996.
14.
GunjiY, NakamuraM, OsawaH, NagayoshiK, NakauchiH, MiuraY, YanagisawaM, SudaT. Human primitive hematopoietic progenitor cells are more enriched in KITlow cells than in KIThigh cells. Blood82: 32833289, 1993.
15.
KatayamaN, ShihJ-P, NishikawaS-I, KinaT, ClarkSC, OgawaM. Stage-specific expression of c-kit protein by murine hematopoietic progenitors. Blood82: 23532360, 1993.
16.
OrizM, WineJW, LohreyN, RuscettiFW, SpenceSE, KellerJr.. Functional characterization of a novel hematopoietic stem cell and its place in the c-kit maturation pathway in bone marrow cell development. Immunity10: 173182, 1999.
17.
DoiH, InabaM, YamamotoY, TaketaniS, MoriS-I, SugiharaA, OgataH, TokiJ, HishaH, InabaK, SogoS, AdachiM, MatsudaT, GoodRA, IkeharaS. Pluripotent hemopoietic stem cells are c-kitlow. Proc Natl Acad Sci U S A94: 25132517, 1997.
18.
LianZ, FengB, SugiuraK, InabaM, YuC, JinT, FanT, CuiY, YasumizuR, TokiJ, AdachiY, HishaH, IkeharaS. c-kitlow pluripotent hemopoietic stem cells form CFU-S on Day 16. Stem Cells17: 3944, 1999.
19.
YamamotoY, YasumizuR, AmouY, WatanabeN, NishioN, TokiJ, FukuharaS, IkeharaS. Characterization of peripheral blood cells in mice. Blood88: 445454, 1996.
20.
BernsteinID, AndrewaRG, ZseboKM. Recombinant human stem cell factor enhances the formation of colonies by CD34+ and CD34+lin− cells, and the generation of colony-forming cell progeny from CD34+lin− cells cultured with interleukin-3, granulocyte colony-stimulating factor, or granulocyte-macrophage colony-stimulating factor. Blood77: 23162321, 1991.
21.
XiaoM, LeemhuisT, BroxmeyerHE, LuL. Influence of combinations of cytokines on proliferation of isolated single cell-sorted human bone marrow hematopoietic progenitor cells in the absence and presence of serum. Exp Hematol20: 276279, 1992.
22.
LuL, XiaoM, ShenR-N, GrigsbyS, BroxmeyerHE. Enrichment, characterization, and responsiveness of single primitive CD34 human umbilical cord blood hematopoietic progenitors with high proliferative and replating potential. Blood81: 4148, 1993.
23.
SienaS, BregniM, BrandoB, RavagnaniF, BonadonnaG, GianniAM. Circulation of CD34+ hematopoietic stem cells in the peripheral blood of high-dose cyclophosphamide-treated patients: Enhancement by intravenous recombinant human granulocyte-macrophage colony-stimulating factor. Blood74: 19051914, 1989.
24.
HaoQ-L, ShahAJ, ThiemannFT, SmogorzewaskaEM, CrooksGM. A functional comparison of CD34+CD38− cells in cord blood and bone marrow. Blood86: 37453753, 1995.
25.
MurrayL, ChenB, GalyA, ChenS, TushinskiR, UchidaN, NegrinR, TricotG, JagannathS, VesoleD. Enrichment of human hematopoietic stem cell activity in the CD34+Thy-1+Lin− subpopulation from human mobilized peripheral blood. Blood85: 368378, 1995.
26.
CraigW, KayR, CutlerRL, LansdorpPM. Expression of Thy-1 on human hematopoietic progenitor cells. J Exp Med177: 13311342, 1993.
27.
MayaniH, LansdorpPM. Thy-1 expression is linked to functional properties of primitive hematopoietic progenitor cells from human umbilical cord blood. Blood83: 24102417, 1994.
28.
KatayamaN, ClarkSC, OgawaM. Growth factor requirement for survival in cell-cycle dormancy of primitive murine lymphohematopoietic progenitors. Blood8: 610616, 1993.
29.
TsujiK, LymanSD, SudoT, ClarkSC, OgawaM. Enhancement of murine hematopoiesis by synergistic interactions between steel factor (ligand for c-kit), interleukin-11. and other early acting factors in culture. Blood79: 28552860, 1992.
30.
SimmonsPJ, AylettGW, NiuttaS, ToLB, JuttnerCA, AsmanLK. c-Kit is expressed by primitive human hematopoietic cells that give rise to colony-forming cells in stroma-dependent or cytokine-supplemented culture. Exp Hematol22: 157165, 1994.
31.
GoreSD, AminS, WengL-J, CivinCI. Steel factor supports the cycling of isolated human CD34+ cells in the absence of other growth factors. Exp Hematol23: 413421, 1995.
32.
LaverJH, AbboudMR, KawashimaI, LearyAG, AshmanLK, OgawaM. Characterization of c-kit expression by primitive hematopoietic progenitors in umbilical cord blood. Exp Hematol23: 15151519, 1995.
33.
BriddellRA, BroudyVC, BrunoE, BrabdtJE, SrourEF, HoffmanR. Further phenotypic characterization and isolation of human hematopoietic progenitor cells using a monoclonal antibody to the c-kit receptor. Blood79: 31593167, 1992.
34.
KawashimaI, ZanjaniED, Almaida-PoradaG, FlakeAW, ZengH, OgawaM. CD34+ human marrow cells that express low levels of kit protein are enriched for long-term marrow-engrafting cells. Blood87: 41364142, 1996.
35.
De JongMO, WagemakerG, WognumAW. Separation of myeloid and erythroid progenitors based on expression of CD34 and c-kit. Blood86: 40764085, 1995.
36.
UoshimaN, OzawaM, KimuraS, TanakaK, WadaK, KobayashiY, KondoM. Changes in c-kit expression and effects of SCF during differentiation of human erythroid progenitor cells. Br J Haematol91: 3036, 1995.
37.
Miyama-InabaM, OgataH, TokiJ, KumaS, SugiuraK, YasumizuR, IkeharaS. Isolation of murine pluripotent hemopoietic stem cells in the Go phase. Biochem Biophys Res Commun147: 687694, 1987.
38.
SogoS, InabaM, OgataH, HishaH, AdachiY, MoriS-I, TokiJ, YamanishiK, KanzakiH, AdachiM, IkeharaS. Induction of c-kit molecules on human CD34+/c-kitlow cells: Evidence for CD34+/c-kitlow cells as primitive hematopoietic stem cells. Stem Cells15: 420429, 1997.
39.
IshidaT, InabaM, HishaH, SugiuraK, AdachiY, NagataN, OgawaR, GoodRA, IkeharaS. Requirement of donor-derived stromal cells in the bone marrow for successful allogeneic bone marrow transplantation: Complete prevention of recurrence of autoimmune diseases in MRL/MP-lpr-lpr mice by transplantation of bone marrow plus bone (stromal cells) from the same donor. J Immunol152: 31193127, 1994.
40.
HishaH, NishinoT, KawamuraM, AdachiS, IkeharaS. Successful bone marrow transplantation by bone grafts in chimeric-resistant combination. Exp Hematol23: 347352, 1995.
41.
HashimotoF, SugiuraK, InoueK, IkeharaS. Major histocompatibility complex restriction between hematopoietic stem cells and stromal cells in vivo.Blood89: 4954, 1997.
42.
SugiuraK, InabaM, HishaH, BorisovK, Sardi-aEE, GoodRA, IkeharaS. Requirement of major histocompatibility complex-compatible microenvironment for spleen colony formation (CFU-S on Day 12 but not on Day 8). Stem Cells15: 461468, 1997.
