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a Gladstone Institute of Virology and Immunology, San Francisco, California, USA;" L' ]5 X3 p% L/ N# n
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b Department of Medicine, University of California, San Francisco, California, USA;
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" ^* E& ^0 j8 }! A: n/ b8 Rc Department of Microbiology and Immunobiology, University of California, San Francisco, California, USA
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8 O) i% u. m, I% d4 w! @4 hKey Words. Hematopoiesis ? Growth factor ? Hematopoietic progenitor ? In vitro ? Marrow stromal cells ? Bone marrow cells
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Correspondence: Joseph M. McCune, M.D., Ph.D., Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158-2261, USA. Telephone: 415-734-5060; Fax: 415-826-8449; e-mail: mmccune@gladstone.ucsf.edu7 A8 z: g3 f8 I3 h
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ABSTRACT
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Growth hormone (GH) and its proximal mediator, insulin-like growth factor I (IGF-I), have been shown to play an important role in T lymphopoiesis . Administration of GH or IGF-I reverses thymic involution and enhances T lymphopoiesis in older rodents and accelerates immune reconstitution in immunodeficient animals . Recently, we extended these observations to humans, demonstrating that GH treatment is associated with increases in thymic mass and circulating na?ve CD4 T cells in adults infected with human immunodeficiency virus, type 1 (HIV-1) . These data suggest that de novo T-cell production may be inducible in immunodeficient humans.& Z. n3 d4 c' c7 f" M2 w) h
1 H* Q# R+ w5 S( AT lymphopoiesis is dependent upon the migration of prethymic bone marrow (BM) progenitor cells to the thymus , and age-related declines in T lymphopoiesis have been attributed to both decreased hematopoietic capacity of BM progenitors and involution of the thymus (reviewed in Miller and Globerson ). Thus, GH may enhance human T lymphopoiesis by acting on cellular targets in the BM and/or in the thymus. BM appears to be an important target of GH action, as demonstrated by rodent studies showing a significant effect of GH on multilineage hematopoiesis. In studies of mice and aging rats, administration of GH and IGF-I facilitates early stages of T-cell development by increasing the number of multilineage BM progenitors and by enhancing the migration and engraftment of progenitor cells into the thymus . Similarly, in vitro analyses showed that GH stimulates erythroid and myeloid colony formation from murine and human BM progenitors. These effects appear to be mediated, at least in part, by IGF-I .
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0 j2 }3 E5 Z& K2 J6 ?1 EIn the current study, we sought to more specifically identify cellular targets of GH and IGF-I action within the human fetal BM (FBM). We hypothesized that GH may stimulate hematopoiesis either through direct effects upon multilineage or lineage-restricted hematopoietic progenitor cells or, indirectly, by inducing FBM stromal cells to produce cytokines that facilitate the survival or maturation of FBM progenitors. We found that GH and IGF-I have direct effects on the proliferation and survival of both multilineage and lineage-committed progenitor cells, and that these hormones also enhance cytokine production by FBM stroma. These findings further delineate the effects of GH and IGF-I within human BM and provide insight into mechanisms that may contribute to GH– and IGF-I–mediated enhancement of hemato-lymphopoiesis.
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MATERIALS AND METHODS
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- E0 T7 ?+ c" d7 bGH Stimulates Proliferation of Primitive Multilineage Hematopoietic Progenitor Cells
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To identify potential GH targets within the FBM, the expression of cell-surface GHR was assessed using a biotinylated antiGHR antibody on freshly acquired FBM mononuclear cells. Various subpopulations of multilineage and lineage-restricted hematopoietic progenitor cells were discriminated on the basis of their phenotypic markers, as described in Figure 1. The frequency of each of these subpopulations in the FBM was determined for six donors (Table 1). As shown in Figure 2A (left panel), GHR was expressed on a sizeable fraction of total FBM mononuclear cells (mean 19.4%, range 15%–28.8% in seven independent experiments). Using antibodies against the lineage markers shown in Figure 1, we found that these progenitor subpopulations expressed varying levels of GHR (Fig. 2A). Incubation of total FBM mononuclear cells or CD34 cells with GH for at least 4 days resulted in a higher yield of total cells relative to untreated controls (p 7 {0 X" p6 ?1 N5 L/ z( d
; X0 ~. q H4 ~) y+ C9 ?( wFigure 1. CD34 progenitor cell subpopulations in FBM. (A): Flow diagram representing multilineage human hematopoiesis. Cell surface markers designate those used to identify the different progenitor cell populations . (B): Flow cytometry plots show gating strategy used for phenotypic data collection. The first panel represents gating for CD34/CD38 populations, after gating on mononuclear cells gated by forward and side scatter (not shown). The large dashed box shows the total CD34 gate. This CD34 population was subdivided using CD38 (small boxes, labeled 34 38– and 34 38 ). The CD34 CD38 population was first subdivided with CD10 (next panel) into CD34 CD38 CD10 and CD34 CD38 CD10– subpopulations. The remaining panels show gating used to discriminate CD34 CD19 , CD34 CD14 , and BrdU cell subpopulations, respectively, after first gating on mononuclear cells (not shown). Abbreviations: BFU-E, burst-forming unit-erythroid; CFU-GEMM, colony-forming unit-granulocyte, erythroid, monocyte, megakaryocyte; CFU-GM, colony-forming unit-granulocyte-monocyte; DC, dendritic cell; FBM, fetal bone marrow; NK, natural killer.! }! \! x- c/ M. } I8 b
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Table 1. Frequency of FBM progenitor subpopulations9 X7 ^! i {5 [' j
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Figure 2. Effects of GH on FBM progenitor cells. (A): Expression of GHR (shaded histograms) relative to isotype control staining (open histograms) after first gating on a mononuclear cell gate. These results are representative of seven independent experiments carried out on FBM progenitor cells from seven different donors. The numbers above the bars represent the percentage of GHR cells, that is, the percentage of cells in given subpopulation with levels of GHR staining above those found with the isotype control. (B): Effect of GH on the yield of cells within different FBM subpopulations as a mean percentage of untreated control cultures (unfilled bars). An increase in the absolute number of many subpopulations is seen after the addition of GH (100–250 ng/ml for 4–8 days) (filled bars) to either total FBM mononuclear cells (BM) or purified CD34 cells (*p / {- x9 S' T7 @, T" d8 ?" {
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GH-associated increases in the total number of hematopoietic progenitor cells could be due to enhanced proliferation or decreased levels of apoptosis. To discriminate between these possibilities, total FBM mononuclear cells or CD34 cells were treated with GH and analyzed by flow cytometry to detect proliferation (BrdU incorporation) and apoptosis (annexin-V binding). Levels of proliferation were significantly increased in the CD34 CD38– subpopulation after GH stimulation of CD34 cells (Fig. 2D), whereas none of the FBM subpopulations showed significant changes in apoptosis (data not shown).
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& T: F Y0 z7 b: j3 ]3 YTo confirm that GH stimulation resulted in an increase in functionally competent human hematopoietic progenitor cells, total FBM mononuclear cells were cultured for 6 days in the presence or absence of GH and then plated into methylcellulose cultures. As shown in Table 2, GH treatment resulted in a statistically significant (p
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Table 2. GH and IGF-I effects on CFU-Cs
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$ C. n, A. h2 W0 QGH Stimulates Proliferation of FBM Stromal Cells. h }/ j) m. d) Z( p4 T5 A F
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The above data indicate that GH may interact directly with and induce the proliferation of primitive multilineage human hematopoietic progenitor cells as well as of lineage-restricted progenitor cells. Given the high expression levels of GHR on CD34 CD14 myeloid progenitor cells, some of which might mature into FBM stromal macrophages , we hypothesized that GH might also indirectly regulate hematopoiesis through the FBM stroma. As a first test of this hypothesis, expression levels of GHR were assessed on recently plated (; T" l1 m7 N, J% d+ c6 g" c
|3 i+ P! V' l, P) AFigure 3. Effects of GH on FBM stromal cells. (A): Representative surface staining of GHR on FBM stromal cells (n = 9, a mean 3.4% of total, range 0.91%–11.5%, were positive for GHR) (second panel). Gates were set using the isotype control (left panel). Many of the GHR cells were also CD45 (n = 9, mean 65.3%, range 25%–97%). GHR CD45 FBM stromal cells are IGFR (n = 3, range 76%–99%) (solid line) whereas GHR CD45– FBM stromal cells are IGFR low or negative (dashed line) (third panel). CD45 GHR FBM stromal cells are also CD14 (n = 3, range 68%–93%) (solid line, right panel). (B): Incubation of FBM stromal cells with GH (100 ng/ml) results in an increase in the total number of total FBM stromal cells, stromal cells that are GHR IGFR CD45 , and stromal cells that are CD14 IGFR CD45 . These panels represent pooled data from four separate experiments. Cell yields in GH-treated cultures are expressed as a mean percentage of untreated control cultures. (C): BrdU incorporation into the FBM stromal cell populations after 1 day in culture with GH addition (100 ng/ml). *p
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Incubation of FBM stromal cultures with exogenous GH for 1 day resulted in an increased yield of stromal cells relative to untreated control cultures (p
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% n: G3 ~; E8 u) s% ~IGF-I Effects on Human Multilineage Hematopoiesis
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GH effects are often mediated through IGF-I . Indeed, in three FBM stromal cultures treated with exogenous GH (100 ng/ml), a significant increase (p ; X% a8 ~& _7 H3 j" B( m# \" g
* R# F3 T- K, e% s1 HTo determine potential cellular targets of IGF-I, IGFR expression was assessed on FBM mononuclear and stromal cells. Surface expression of IGFR was detected on CD45 CD14 myeloid stromal cells (see above, Fig. 3A) and on a large fraction of FBM progenitor cells (Fig. 4A). Additionally, mature CD10 CD45– fibroblast-like stromal cells expressed a low level of IGFR (data not shown).
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% \, z r; F2 L# j% nFigure 4. Effects of IGF-I on FBM progenitor cells. (A): Expression of IGFR (shaded histograms) on FBM mononuclear subpopulations relative to isotype control staining (open histograms). These results are representative of three independent experiments carried out on FBM cells from three different donors. The numbers above the bars represent the percentage of IGFR cells, that is, the percentage of cells in given subpopulation with levels of IGFR staining above those found with the isotype control. (B): Effect of IGF-I on the yield of cells within different FBM mononuclear subpopulations as a percentage of the mean of the untreated control cultures (unfilled bars). An increase in the absolute number of many subpopulations is seen after the addition of IGF-I (100 ng/ml) (filled bars) to either total FBM mononuclear cells or CD34 cells. These results represent pooled data from eight independent experiments carried out on FBM progenitor cells from eight different donors. (C): Effect of IGF-I on the percentage of apoptotic (annexin-V staining) cells within FBM mononuclear subpopulations as a percentage of the mean of the untreated control cultures (unfilled bars). These results represent pooled data from eight independent experiments carried out on FBM progenitor cells from eight different donors. In (B, C), *p 6 u$ g6 {2 d/ t% |) v4 u4 {; J
) e& H! [) _8 R/ m, |8 yTo determine whether these cells were functionally responsive to IGF-I, total FBM mononuclear cells or purified CD34 mononuclear cells were incubated with IGF-I. Treatment with IGF-I for 4–8 days resulted in an increase in the yield of FBM CD34 progenitor cells relative to untreated control cultures (p
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In contrast to the effects of GH, treatment of FBM cells with IGF-I resulted not only in an increase in CFU-GM and CFU-GEMM but also in an increase in BFU-E (p
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GH and IGF-I Induce Cytokine Secretion by FBM Stromal Cells* b$ P$ ]+ F! w
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We hypothesized that GH and IGF-I might facilitate multilineage hematopoiesis by inducing the secretion of key hematopoietic cytokines from FBM stromal cells. To investigate this possibility, FBM stroma cultures were plated in replicate, stimulated with exogenous GH or IGF-I for 1 day, treated with brefeldin A to block secretion of induced cytokines, and then assessed by flow cytometry for the presence of intracellular IL-3. Relative to untreated cultures (Fig. 5, upper panels), IL-3 production was consistently stimulated by IGF-I (Fig. 5, middle panels) and, to a more variable and lesser degree, by GH (Fig. 5, lower panels). When lineage markers were included in the analysis, most IL-3–producing cells were found to be nonhematopoietic (CD45–CD10 ) mature fibroblast-like FBM stromal cells (data not shown). Although increases in IL-3 production were observed in four of five stromal cultures incubated with GH (average = 2.2-fold) and in five of five cultures incubated with IGF-I (average = 5.9-fold), these changes were variable, even within a given experiment (and as evidenced in the replicates of Fig. 5). In addition to IL-3, we observed sporadic increases in the expression of other hematopoietic cytokines (e.g., IL-6, IL-7, and SCF; data not shown). In aggregate, these results suggest that GH may act, directly or indirectly, to induce both IGF-I and IL-3 from FBM stroma, but that the stromal cell(s) making these secondary mediators are rare.5 u2 l5 e) J5 o6 t6 w$ q4 k
& F- P' }5 J* [3 c4 aFigure 5. Induction of IL-3 production by GH and IGF-I. FBM stromal cells were incubated in triplicate with medium alone (upper panels), 100 ng/ml IGF-I (middle panels), or 100 ng/ml GH (lower panels) for 24 hours, and then assessed by flow cytometry for the presence of intracellular IL-3. Triplicate results from a single donor are displayed. This experiment is representative of five independent experiments carried out with cells from five different donors. Abbreviations: FBM, fetal bone marrow; GH, growth hormone; IGF-I, insulin-like growth factor I; IL, interleukin.0 a" h& I9 y5 {4 y, R# n$ \
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DISCUSSION
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u5 E6 c# |! g9 C2 AThis study was supported by National Institutes of Health (NIH) grants R37 AI40312 and R01 AI43864 (to J.M.M.) and K08 AI01597 (to L.A.N). J.M.M. is an Elizabeth Glaser Pediatric AIDS Foundation Scientist and a recipient of the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research and of the NIH Director’s Pioneer Award., ?+ b/ |6 ]0 ]- g! L4 c4 C j0 Q
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