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Blood, Vol. 92 No. 1 (July 1), 1998:
pp. 1-3
Thrombopoietin and the Hematopoietic Stem Cell
By
Kenneth Kaushansky
From the Division of Hematology, University of Washington, Seattle.
SPECIAL FOCUS INTRODUCTION
THE FACTORS that contribute to the
maintenance of hematopoietic stem cells and their commitment to various
hematopoietic lineages have been sought for many decades.
Unfortunately, our present understanding of this process is far from
complete. Accumulating evidence suggests that steel factor (SF; also
termed stem cell factor, mast cell growth factor, or c-kit ligand) is
at least one of the proteins that contributes to the maintenance of
normal stem cell numbers. Its genetic elimination in mice, or that of its receptor c-kit, leads to a profound reduction in the number of
hematopoietic stem cells, assayed as marrow cells that can persistently
repopulate all of hematopoiesis in a lethally irradiated recipient.1 In addition, the administration of SF to mice
expands the number of transplantable hematopoietic stem
cells.2 Despite these results, SF alone cannot maintain the
numbers of stem cells in vitro,3 suggesting that these in
vivo effects are due to the interaction of SF with other cytokines. Two
proteins thought to play such a role are FLT-3 ligand (FL) and
interleukin-11 (IL-11). Genetic elimination of the FLT3 receptor leads
to a fivefold reduction in the number of long-term repopulating
hematopoietic stem cells,4 although administration of FL
has not been reported to increase the number of stem cells. In contrast
to the SF/c-kit and FL/FLT3 receptor systems, genetic elimination of
the IL-11 receptor fails to affect hematopoietic stem cell
numbers5; rather, the evidence that IL-11 affects stem
cells derives almost entirely from in vitro expansion experiments.
Neither SF, FL, or their combination are sufficient for maintaining the
number of hematopoietic stem cells in serum-free
culture.6,7 However, the addition of IL-11 to either SF or
FL maintains, and the presence of all three cytokines modestly expands
the number of transplantable stem cells in serum-free ex vivo
cultures.6,7 Several other cytokines have been tested for
their capacity to maintain or expand the number of hematopoietic stem
cells, including IL-1, IL-3, IL-6, IL-12, and the blockade of
transforming growth factor- (TGF-),8-11 but none have
proven essential by the rigorous criteria noted above, genetic
elimination reducing, or forced expression expanding the number of
marrow cells capable of long-term hematopoietic repopulation. Thus, it
is of great interest when another hematopoietic cytokine is reported to
directly affect the hematopoietic stem cell.
The recent cloning of thrombopoietin and characterization of the
recombinant protein fulfilled its predicted role as the primary regulator of megakaryocyte and platelet development. Alone,
thrombopoietin stimulates megakaryocyte colony growth from marrow
progenitors, stimulates the maturation of immature megakaryocytes, and
supports the formation of functional platelets.12-14
However, soon after the recombinant protein became available, evidence
began to emerge that thrombopoietin plays a wider role in hematopoiesis
than initially anticipated, exerting profound effects on primitive
hematopoietic cells. A diverse range of studies have supported this
concept, including studies of thrombopoietin receptor expression and
function, the administration of the hormone to animals, genetic
elimination of thrombopoietin or its receptor, and single cell in vitro
tracking experiments.
The thrombopoietin receptor (c-mpl) was first recognized as the
transforming oncogene (v-mpl) of the murine myeloproliferative leukemia virus, an agent that induces not only megakaryocytic hyperplasia but a pan-myeloid disorder.15 Consistent with
this effect, the normal receptor is expressed not only on
megakaryocytes and platelets, but also on a large fraction of
CD34+ cells,16 from which thrombopoietin
enhances megakaryocyte formation.17 Administration of
thrombopoietin to normal animals expands the number of marrow and
splenic progenitors of all hematopoietic lineages, and accelerates
their recovery if given following myelosuppressive therapy.18,19 Furthermore, in addition to the profound
thrombocytopenia and reduced marrow levels of megakaryocytes and their
progenitors, mice carrying targeted deletions of the genes for
thrombopoietin or its receptor were found to possess greatly reduced
numbers of progenitors committed to the erythroid and myeloid
lineages.20,21 However, it was unclear whether these
findings were the result of thrombopoietin affecting the committed
hematopoietic progenitor, or due to a direct effect on cells at an
earlier stage of development.
While these in vivo experiments were being conducted, the direct
effects of thrombopoietin on candidate populations of stem cells were
also being tested. Ku et al22 found that adding
thrombopoietin to either IL-3 or SF speeds entry of
post-5FU/lin /ly6+/kit+ murine
cells into the cell cycle, and greatly augments the development of
progenitor cells committed to all hematopoietic lineages. Sitnicka et
al23 arrived at the same conclusions using an extremely
enriched population of hematopoietic stem cells. As these latter
experiments were conducted in single cell cultures, thrombopoietin
appeared to exert a direct effect on primitive hematopoietic cells, at least in vitro.
Two more recent studies directly address this question. Kimura et
al24 showed that targeted disruption of the mpl
gene greatly reduces the number of CFU-Sd12, and the marrow
cells of the nullizygous mice were markedly inferior to those derived
from wild-type littermates in a competitive repopulation assay of stem
cell activity. And in this issue of Blood, Solar et
al25 present three lines of evidence that firmly establish
an important role for thrombopoietin in stem cell physiology. Using an
mpl-specific antibody to divide murine
AA4+/Sca+/kit+ fetal liver cells or
linlo/Sca+/kit+ adult marrow cells
into mpl+ and mpl fractions, these
investigators demonstrated that essentially all of the hematopoietic
repopulating activity (assessed at 24 weeks) resides in the
mpl+ subfraction. Next, human marrow
CD34+/CD38/mpl+ cells were shown
to engraft SCID-hu bone mice far more efficiently than
CD34+/CD38/mpl cells.
Finally, Solar et al confirmed and extended the work of Kimura et al,
quantifying the engraftment defect displayed by marrow cells from
mpl nullizygous mice, a deficiency quite similar in magnitude
(sevenfold reduction in repopulating units) to that found in FLT3- and
SF-deficient mice.
Thus, as thrombopoietin is the sole ligand for the mpl receptor, it is
now firmly and directly established that the hormone affects
hematopoietic stem cells. There appear to be at least three immediate
implications of this conclusion. First, the administration of
thrombopoietin may evoke a far greater effect on hematopoietic recovery
than initially anticipated. This prediction has been substantiated, at
least in many preclinical trials of the agent,26-28 and it
would seem prudent that clinical trials should be designed with this
possibility in mind. Second, thrombopoietin could provide an important
adjunct in attempts to expand the numbers of hematopoietic stem cells
for clinical use. The use of umbilical cord blood cells for
transplantation and stem cells of several origins in gene therapy
protocols have provided an important impetus to expand primitive
hematopoietic cells. Evidence of the capacity of thrombopoietin to
augment stem cell expansion is accumulating; the hormone is the most
potent single agent at expanding long-term culture initiating cells in
serum-free culture,29 a surrogate assay for the human hematopoietic stem cell, and the combination of FL plus thrombopoietin greatly expands the output of these cells in long-term umbilical cord
blood cell cultures.30 Moreover, agents such as
thrombopoietin, which accelerate stem cell entry into the cell
cycle,22,23 are particularly attractive for the expansion
of stem cells used for gene therapy, where target cell proliferation is
required for successful retroviral vector integration. Third, the
ability of thrombopoietin to support the survival and proliferation of hematopoietic stem cells may also herald adverse effects if the hormone
is used in patients with myeloproliferative disorders. Similar warnings
were sounded with the use of GM-CSF and G-CSF after therapy for acute
myeloid leukemia, concerns that have not been realized.31
However, G- and GM-CSF do not affect the hematopoietic stem cell, the
likely cellular origin of most cases of myeloproliferative disease.
Thus, once again, we need to carefully monitor the administration of
thrombopoietin to such patients.
Our understanding of stem cell biology has advanced with the
demonstration that thrombopoietin is one of the factors that supports
the survival and proliferation of these intriguing cells. However, many
questions remain unanswered. The nature of the intracellular signals
initiated by thrombopoietin and the other proteins that affect stem
cell development are unknown, as are how these events interact with the
developmental programs initiated by transcription factors such as
SCL/TAL1, Rbtn-2, or GATA-232 to affect hematopoietic stem
cell expansion and lineage determination. It is now up to basic
scientists and clinical investigators to advance our understanding of
this process and to exploit these effects for therapeutic benefit.
 |
FOOTNOTES |
Address reprint requests to Kenneth Kaushansky, MD, Division of
Hematology, Box 357710, University of Washington, Seattle, WA 98195.
| |
REFERENCES |
1.
Broudy VC:
Stem cell factor and hematopoiesis.
Blood
90:1345,
1997[Free Full Text]
2.
Bodine DM,
Seidel NE,
Zsebo KM,
Orlic D:
In vivo administration of stem cell factor to mice increases the absolute number of pluripotent stem cells.
Blood
82:445,
1993[Abstract]
3.
Li CL,
Johnson GR:
Stem cell factor enhances the survival but not the self-renewal of murine hematopoietic long-term repopulating cells.
Blood
84:408,
1994[Abstract/Free Full Text]
4.
Yonemura Y,
Ku H,
Lyman SD,
Ogawa M:
In vitro expansion of hematopoietic progenitors and maintenance of stem cells: Comparison between flt3/flk2 ligand and kit ligand.
Blood
89:1915,
1997[Abstract/Free Full Text]
5.
Nandurkar HH,
Robb L,
Tarlinton D,
Barnett L,
Köntgen F,
Begley CG:
Adult mice with targeted mutation of the interleukin-11 receptor (IL11Ra) display normal hematopoiesis.
Blood
90:2148,
1997[Abstract/Free Full Text]
6.
Miller CL,
Eaves CJ:
Expansion in vitro of adult murine hematopoietic stem cells with transplantable lympho-myeloid reconstituting ability.
Proc Natl Acad Sci USA
94:13648,
1997[Abstract/Free Full Text]
7.
Mackarehtschian K,
Hardin JD,
Moore KA,
Boast S,
Goff SP,
Lemischka IR:
Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors.
Immunity
3:147,
1995[Medline]
[Order article via Infotrieve]
8.
Peters SO,
Kittler ELW,
Ramshaw HS,
Quesenberry PJ:
Ex vivo expansion of murine marrow cells with interleukin (IL)-3, IL-6, IL-11 and stem cell factor leads to impaired engraftment in irradiated hosts.
Blood
87:30,
1996[Abstract/Free Full Text]
9.
Van der Loo JCM,
Ploemacher RE:
Marrow and spleen-seeding efficiencies of all murine hematopoietic stem cells are decreased by preincubation with hematopoietic growth factors.
Blood
85:2598,
1995[Abstract/Free Full Text]
10.
Muench MO,
Firpo MT,
Moore MAS:
Bone marrow transplantation with interleukin-1 plus kit-ligand ex vivo expanded bone marrow accelerates hematopoietic reconstitution in mice without the loss of stem cell lineage and proliferative potential.
Blood
81:3463,
1993[Abstract]
11.
Soma T,
Yu JM,
Dunbar CE:
Maintenance of murine long-term repopulating stem cells in ex vivo culture is affected by modulation of transforming growth factor- but not macrophage inflammatory protein-1 activities.
Blood
87:4561,
1996[Abstract/Free Full Text]
12.
Kaushansky K:
Thrombopoietin: The primary regulator of platelet production.
Blood
86:419,
1995[Free Full Text]
13.
Kaushansky K,
Lok S,
Holly RD,
Broudy VC,
Lin N,
Bailey MC,
Forstrom JW,
Buddle M,
Oort PJ,
Hagen FS,
Roth GJ,
Papayannopoulou T,
Foster DC:
Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin.
Nature
369:568,
1994[Medline]
[Order article via Infotrieve]
14.
Cramer EM,
Norol F,
Guichard J,
Breton-Gorius J,
Vanchenker W,
Massé J-M,
Debili N:
Ultrastructure of platelet formation by human megakaryocytes cultured with the Mpl ligand.
Blood
89:2336,
1997[Abstract/Free Full Text]
15.
Souyri M,
Vigon I,
Penciolelli J-F,
Tambourin P,
Wendling F:
A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors.
Cell
63:1137,
1990[Medline]
[Order article via Infotrieve]
16.
Vigon I,
Mornon J-P,
Cocault L,
Mitjavila M-T,
Tambourin P,
Gisselbrecht S,
Souyri M:
Molecular cloning and characterization of MPL, the human homolog of the v-mpl oncogene: Identification of a member of the hematopoietic growth factor receptor superfamily.
Proc Natl Acad Sci USA
89:5640,
1992[Abstract]
17.
Zeigler FC,
de Sauvage F,
Widmer HR,
Keller GA,
Donahue C,
Schreiber RD,
Malloy B,
Hass P,
Eaton D,
Matthews W:
In vitro megakaryocytopoietic and thrombopoietic activity of c-mpl ligand (TPO) on purified murine hematopoietic stem cells.
Blood
84:4045,
1994[Abstract/Free Full Text]
18.
Kaushansky K,
Lin N,
Grossmann A,
Humes J,
Sprugel KH,
Broudy VC:
Thrombopoietin expands erythroid, granulocyte-macrophage and megakaryocytic progenitor cells in normal and myelosuppressed mice.
Exp Hematol
23:265,
1996
19.
Farese AM,
Hunt P,
Grab LB,
MacVittie TJ:
Combined administration of recombinant human megakaryocyte growth and development factor and granulocyte colony-stimulating factor enhances multi-lineage hematopoietic reconstitution in nonhuman primates after radiation induced marrow aplasia.
J Clin Invest
97:2145,
1996[Abstract/Free Full Text]
20.
Alexander WS,
Roberts AW,
Nicola NA,
Li R,
Metcalf D:
Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietin receptor c-Mpl.
Blood
87:2162,
1996[Abstract/Free Full Text]
21.
Carver-Moore K,
Broxmeyer HE,
Luoh SM,
Cooper S,
Peng J,
Burstein SA,
Moore MW,
deSauvage FJ:
Low levels of erythroid and myeloid progenitors in thrombopoietin and mpl-deficient mice.
Blood
88:803,
1996[Abstract/Free Full Text]
22.
Ku H,
Yonemura Y,
Kaushansky K,
Ogawa M:
Thrombopoietin, the ligand for the Mpl receptor, synergizes with steel factor and other early-acting cytokines in supporting proliferation of primitive hematopoietic progenitors of mice.
Blood
87:4544,
1996[Abstract/Free Full Text]
23.
Sitnicka E,
Lin N,
Priestley GV,
Fox N,
Broudy VC,
Wolf NS,
Kaushansky K:
The effect of thrombopoietin on the proliferation and differentiation of murine hematopoietic stem cells.
Blood
87:4998,
1996[Abstract/Free Full Text]
24.
Kimura S,
Roberts AW,
Metcalf D,
Alexander WS:
Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin.
Proc Natl Acad Sci USA
95:1195,
1998[Abstract/Free Full Text]
25.
Solar GP,
Kerr WG,
Zeigler FC,
Hess D,
Donahue C,
de Sauvage FC,
Eaton DL:
Role of c-Mpl in early hematopoiesis.
Blood
92:4,
1998[Abstract/Free Full Text]
26.
Kaushansky K,
Broudy VC,
Grossmann A,
Humes J,
Lin N,
Ren H-P,
Bailey MC,
Papayannopoulou T,
Forstrom JW,
Sprugel KH:
Thrombopoietin expands erythroid progenitors, increases red cell production, and enhances erythroid recovery after myelosuppressive therapy.
J Clin Invest
96:1683,
1995[Medline]
[Order article via Infotrieve]
27.
Neelis KJ,
Qingliang L,
Thomas GR,
Cohen BL,
Eaton DL,
Wagemaker G:
Prevention of thrombocytopenia by thrombopoietin in myelosuppressed rhesus monkeys accompanied by prominent erythropoietic stimulation and iron depletion.
Blood
90:58,
1997[Abstract/Free Full Text]
28.
Akahori H,
Shibuya K,
Obuchi M,
Nishizawa Y,
Tsuji A,
Kabaya K,
Kusaka M,
Ohashi H,
Tsumura H,
Kato T,
Miyazaki H:
Effect of recombinant human thrombopoietin in nonhuman primates with chemotherapy-induced thrombocytopenia.
Br J Haematol
94:722,
1996[Medline]
[Order article via Infotrieve]
29.
Petzer AL,
Zandstra PW,
Piret JM,
Eaves CJ:
Differential cytokine effects on primitive (CD34+CD38 ) human hematopoietic cells: Novel responses to Flt-3 ligand and thrombopoietin.
J Exp Med
183:2551,
1996[Abstract]
30.
Piacibello W,
Sanavio F,
Garetto L,
Severino A,
Bergandi D,
Ferrario J,
Fagioli F,
Berger M,
Aglietta M:
Extensive amplification and self-renewal of human primitive hematopoietic stem cells from cord blood.
Blood
89:2653,
1997
31.
Rowe JM,
Liesveld JL:
Hematopoietic growth factors in acute leukemia.
Leukemia
11:328,
1997[Medline]
[Order article via Infotrieve]
32.
Shivdasani RA,
Orkin SH:
The transcriptional control of hematopoiesis.
Blood
87:4025,
1996[Free Full Text]
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Article
References