Effects of growth hormone therapeutic supplementation on hematopoietic stem/progenitor cells in children with growth hormone deficiency: focus on proliferation and differentiation capabilities

• Published in: Endocrine Vol. 50; no. 1; pp. 162 - 175
• Main Authors: Kawa, M. P., Stecewicz, I., Piecyk, K., Pius-Sadowska, E., Paczkowska, E., Rogińska, D., Sobuś, A., Łuczkowska, K., Gawrych, E., Petriczko, E., Walczak, M., Machaliński, B.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.09.2015
• Subjects: Adolescent; Cell Cycle - drug effects; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Child; Child, Preschool; Diabetes; Endocrinology; Gene Expression - drug effects; Gene Expression Profiling; Hematopoietic Stem Cells - drug effects; Hormone Replacement Therapy; Human Growth Hormone - administration & dosage; Human Growth Hormone - deficiency; Human Growth Hormone - pharmacology; Humanities and Social Sciences; Humans; Insulin-Like Growth Factor I - drug effects; Internal Medicine; Medicine; Medicine & Public Health; multidisciplinary; Original; Original Article; Receptors, Somatotropin - drug effects; Science; Hematopoietic stem/progenitor cells; Hematopoiesis; Growth hormone deficiency; Growth hormone deficiency in children
• ISSN: 1355-008X; 1559-0100
• DOI: 10.1007/s12020-015-0591-0

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.