Abstract
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 cycle-propagating 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s12020-015-0591-0) contains supplementary material, which is available to authorized users.
Highlights
Growth hormone (GH) is a pleiotropic hormone important for modulation of physiological processes [1]
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
There is a lack of studies providing the evidence that GH receptor (GHR) is expressed in CD34?-enriched hematopoietic progenitor cells (HPCs) from Peripheral blood (PB) of GHD children
Summary
Growth hormone (GH) is a pleiotropic hormone important for modulation of physiological processes [1]. GH exerts its anabolic effects largely indirectly via stimulation of insulin-like growth factor-1 (IGF1) production. Acting in autocrine/paracrine manner, GH binds to the specific receptor (GHR), which induces intracellular signaling pathways leading to differential gene expression [1]. The classical examples of IGF1-independent actions mediated through GHR include ovarian preantral follicle development [2] or activation of chondrocyte stem cells for chondrocyte generation at bone growth plate [3]. In vitro studies indicate that neural stem cell activation by GH does not require IGF1 [4]. GH is a potent modulator of hematopoietic system, which has been described in numerous experimental studies. GH binds to GHR expressed on hematopoietic/immune
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