Growth Hormone–Induced Stimulation of Multilineage Human Hematopoiesis (original) (raw)
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Biology of Blood and Marrow Transplantation, 2004
To determine whether circulating insulin-like growth factor (IGF)-I has a role in hematopoiesis, we examined hematologic parameters in mice with markedly reduced serum levels resulting from a liver-specific inactivation of the IGF-I gene. These mice have normal postnatal growth and development, suggesting that local production of IGF-I can maintain anabolic effects. Liver-specific IGF-I-deficient (LID) mice were compared with control littermates with regard to hematopoietic parameters. Spleen cellularity was decreased in the LID mice compared with control mice. Spleen myeloid progenitors, as determined by colony-forming units-granulocyte/ monocyte (CFU-GM) and colony-forming units-high proliferative potential (CFU-HPP), were significantly decreased in the LID mice. Immune parameters, as indicated by the absolute number of B and T cells, did not significantly differ between the knockout and control mice. In contrast to the decreased cellularity and myelopoiesis in the spleen, bone marrow cellularity was not different between the 2 groups, but the total femoral content of CFU-GM and CFU-HPP was significantly increased in the LID mice. The decrease in splenic myelopoiesis was not due to the inability of progenitors to exit the bone marrow, because CFU-GM and burst-forming units-erythroid were significantly increased in the blood of LID mice compared with normal littermates. Administration of exogenous IGF-I to the LID mice for 4 days partially restored myelopoietic parameters in the spleen. Liver production of IGF-I and, therefore, normal serum levels of this hormone, although not necessary for general organ growth and development, seems necessary for survival or transition of myeloid progenitors into the spleen.
Journal of Clinical Oncology, 1991
Growth hormone (GH) and insulin-like growth factor-I (IGF-I) play important roles in erythropoiesis and erythropoietin (EPO) secretion. We examined the effects of GH and IGF-I on EPO production in adult rat kidney and liver in vivo and in vitro. Male Wistar rats aged 8-10 weeks were used. Recombinant human GH (hGH) was continuously infused (20 µg/kg per h) subcutaneously for 48 h using a micro-osmotic infusion pump. Octreotide (10 µg/kg) was subcutaneously injected every 12 h beginning 12 h before the hGH treatment. GH increased plasma EPO levels earlier than it increased plasma IGF-I levels. At 24 h, the IGF-I content in the liver and kidney was increased from 172•8 14•6 to 232•6 17•8 ng/g tissue (means S.E.) and from 53•8 3•1 to 112•8 7•2 ng/g tissue, respectively. The EPO content in the liver was increased from 7•5 1•2 to 15•1 1•4 mIU/g tissue at 48 h, whereas the EPO content in the kidney was decreased at 12, 24, and 48 h after the start of hGH treatment. When the kidneys were organ-cultured, hGH considerably decreased EPO levels in the culture medium in a dose-related manner. The addition of anti-hGH IgG blunted the GH-induced inhibition of EPO secretion from the kidneys. IGF-I also decreased EPO levels in the medium in a dose-related manner. The addition of anti-IGF-I IgG blunted the IGF-I-induced inhibition of EPO secretion from the kidneys, whereas the GH-induced inhibition of EPO secretion was not affected. These findings suggest that both hGH and IGF-I have direct inhibitory effects on EPO secretion from adult rat kidneys.
Leukemia, 1998
The role of insulin (INS), and insulin-like growth factor-I (IGF-I) in the regulation of human erythropoiesis is not completely understood. To address this issue we employed several complementary strategies including: serum free cloning of CD34 ؉ cells, RT-PCR, FACS analysis, and mRNA perturbation with oligodeoxynucleotides (ODN). In a serum-free culture model, both INS and IGF-I enhanced survival of CD34 ؉ cells, but neither of these growth factors stimulated their proliferation. The influence of INS and IGF-I on erythroid colony development was dependent on a combination of growth factors used for stimulating BFU-E growth. When BFU-E growth was optimally stimulated with erythropoietin (EpO) ؉ kit ligand (KL) the large erythroid colonies developed normally even in the absence of INS or IGF-I. However, the addition of both of these growth factors slightly enhanced colony size. On the other hand, if eruthroid colonies were stimulated suboptimally with EpO + IL-3 only, INS or IGF-I increased the number of small erythroid bursts by ෂ30%. Both INS and IGF-I activated signal transduction in maturing human erythropoietic cells as determined by phosphorylation of the insulin receptor substrate-2 (IRS-2) protein. We also found by RT-PCR that mRNA coding for INS-R is expressed in FACS sorted CD34 ؉ , c-kit-R ؉ marrow cells, and in cells isolated from BFU-E and CFU-GM colonies. Expression of INS-R protein on these cells was subsequently confirmed by cytofluorometry. In contrast, the receptor for insulin-like growth factor-I (IGF-IR) was not detected on CD34 ؉ cells, and was first easily detectable on more differentiated cells derived from day 6 BFU-E and CFU-GM colonies. We conclude that INS and IGF-I may be survival factors for human CD34 ؉ cells, but are not required during early erythropoiesis. In contrast, both growth factors may play some role at the final stages of erythroid maturation.
Journal of Neuroimmunology, 1992
The insulin-like growth factors I and II (IGF-I and IGF-II) promote proliferation and differentiation of many cell types. We report that recombinant IGF-I and IGF-II augment both the lectin-and anti-CD3-induced proliferation of human peripheral blood mononuclear ceils (PBMC) at concentrations proportional to their binding affinities. IGF-I and IGF-II also augmented the lectin-induced proliferation of purified T lymphocytes. Effects of IGF-I were found in cultures of T cells vigorously depleted for monocytes and supplemented with saturating concentrations of interleukin-1. The latter results indicate that the effect of IGF-I on the proliferation of T lymphocytes can occur independent of monocytes or monocyte-derived factors.
Endocrine, 2015
We investigated the direct effects of growth hormone (GH) replacement therapy (GH-RT) on hematopoiesis in children with GH deficiency (GHD) with the special emphasis on proliferation and cell cycle regulation. Peripheral blood (PB) was collected from sixty control individuals and forty GHD children before GH-RT and in 3rd and 6th month of GH-RT to measure hematological parameters and isolate CD34 ?-enriched hematopoietic progenitor cells (HPCs). Selected parameters of PB were analyzed by hematological analyzer. Moreover, collected HPCs were used to analyze GH receptor (GHR) and IGF1 expression, clonogenicity, and cell cycle activity. Finally, global gene expression profile of collected HPCs was analyzed using genome-wide RNA microarrays. GHD resulted in a decrease in several hematological parameters related to RBCs and significantly diminished clonogenicity of erythroid progenies. In contrast, GH-RT stimulated increases in clonogenic growth of erythroid lineage and RBC counts as well as significant up-regulation of cell cyclepropagating genes, including MAP2K1, cyclins D1/E1, PCNA, and IGF1. Likewise, GH-RT significantly modified GHR expression in isolated HPCs and augmented systemic IGF1 levels. Global gene expression analysis revealed significantly higher expression of genes associated with cell cycle, proliferation, and differentiation in HPCs from GH-treated subjects. (i) GH-RT significantly augments cell cycle progression in HPCs and increases clonogenicity of erythroid progenitors; (ii) GHR expression in HPCs is modulated by GH status; (iii) molecular mechanisms by which GH influences hematopoiesis might provide a basis for designing therapeutic interventions for hematological complications related to GHD.
Cascade transactivation of growth factor receptors in early human hematopoiesis
Blood, 1993
Highly purified progenitors (including erythroid [BFU-E], granulo-monocytic [CFU-GM], multipotent [CFU-GEMM] progenitors, as well as multipotent progenitors with selfrenewal capacity [CFU-B]) express high-affinity growth factor receptors (GFRs), with prevalent interleukin-3 receptors (IL-3Rs) (2,70O/cell), a 210-fold lower number of IL-6Rs (1 45/cell) and granulocyte-macrophage colonystimulating factor receptors (GM-CSFRs) (300/cell), and a barely detectable level of erythropoietin (Ep) receptors (75/ cell). Hematopoietic growth factor (HGF) dosages inducing peak clonogenetic effects are associated with partial/subtotal occupancy of the homologous HGF receptor (HGFR). Cross-reactivity between GFRs and heterologous GFs (including IL-6, IL-3, GM-CSF, Ep, and thekitligand [KL]) was explored by competition experiments on purified progenitors with radiolabeled and excess cold HGFs at + 4°C. No crossreaction was observed between IL-6R. IL-3R. EpR, and the heterologous GFs, whereas the GM-CSFR showed crossreactivity with IL-3 and, to a lesser extent, KL. Modulation of GFRs was examined after 18 or 40 hours of incubation with GF(s) at 37%, followed by ligand-binding assay at 20°C. IL-6, IL-3. GM-CSF, and Ep induce a marked down-EMATOPOIESIS is a multistep cell proliferation/dif-H ferentiation process that is sustained by a pool of stem cells. The stem elements can self-renew and differentiate into progenitors.'-4 These progenitors are committed to specific lineages and are functionally defined as colony-or burstforming units (CFUs or BFUs), ie, progenitors ofthe erythroid series (BFU-E or CFU-E), the granulocyte-monocytic lineage (CFU-GM), and multipotent CFU for the GM, erythroid, and megakaryocytic series (CFU-GEMM).I4 The progenitors in turn differentiate into morphologically recognizable precursors that mature to terminal elements circulating in peripheral blood. A group of glycoprotein hematopoietic growth factors (HGFs), termed colony stimulating factors (CSFs) or interleukins (ILs), control the survival, proliferation, and differentiation of stem and/or progenitor cells. In addition, they affect a variety of functional activities of mature/terminal cells.'-4
Growth Hormone & IGF Research, 2011
Background: There are very few laboratory markers which reflect the biological sensitivity of children to recombinant human growth hormone (rhGH) treatment. Genome-wide transcriptional changes in peripheral blood mononuclear cells (PBMC) have been widely used as functional readout for different pharmacological stimuli. Objective: To characterize transcriptional changes in PBMC induced by rhGH during a routine short-term IGF-I generation test (IGFGT) in children with growth disorders. Materials and methods: Blood was obtained for IGF-I determination and RNA-preparation from PBMC of 12 children before and after 4 days treatment with 30 μg rhGH/kg body weight/day s.c. Transcriptional changes were assessed by cDNA-microarrays in the first six children. Selected genes were validated in all 12 cases by RT-qPCR. Results: Serum IGF-I rose in all patients except one (p b 0.0001), confirming biological response to rhGH. Unsupervised microarray data analysis in the first six children revealed 313 transcripts with abundant transcriptional changes but considerable inter-individual variability of response patterns. Many patients showed a large cluster of up-regulated genes, including EGR1, EGR2, FOS and to a lesser extent STAT2 and 5b. Exemplarily, EGR1, EGR2 and FOS data were independently reproduced by RT-qPCR. Gene ontology analysis revealed that pathways involved in cell proliferation and immune functions were significantly over represented. Conclusion: The IGFGT is a suitable method for measuring reproducible and biologically conclusive transcriptional changes in PBMC. As our unsupervised data analysis strategy exposed a considerable inter-individual variability of response profiles a search for molecules of diagnostic and even prognostic value needs to be based on large long-term studies.