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

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.

Growth hormone and hematopoiesis: A retrospective analysis on a large cohort of children with growth hormone deficiency

“…GHT has proven to have a marked effect on erythroid progenitor precursors, but negligible effects on peripheral blood cells. Indeed, a significant impact of GH on hematopoietic progenitor cells was documented in 40 GHD children after 3 and 6 months of GHT [22]. Similarly, Kotzmann et al showed that 11 adult patients had hematopoietic precursor cells in the lower normal range.…”

“…Discordant data also come from studies on the effect of GHT on hematopoiesis and few large-scale studies or ones with a long follow-up have been reported in children. The effect of GHT on hematopoietic progenitor cells [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22], as well as on erythropoiesis indices in both adults [21,23] and children affected by GHD [2,20,24,25] has been documented. However, some studies document a significant impact of GHT on erythropoiesis indices exclusively in patients with anemia and not in the totality of patients [19].…”

Long-term effects of growth hormone (GH) replacement therapy on hematopoiesis in a large cohort of children with GH deficiency

“…Indeed, some studies reported normocytic anemia in untreated GHD adults [8,10] and children [7,[9][10][11], while others reported low hematopoietic precursor cells but not anemia in GHD [14]. However, most authors reported a beneficial effect of GH replacement therapy on red cells with an increase of Hb levels [7-11, 13, 17], red cells mass [12,13], and hematopoietic precursors number [14].…”

“…Human studies revealed that GHD in both adults and children can be associated with an impairment of erythropoiesis leading to normocytic anemia [7][8][9][10][11], reduced red cell mass [12,13], or reduced erythroid precursor cells number [14], which improved after GH treatment [7][8][9][10][11][12][13][14].…”

“…Moreover, GH therapy has been associated with increased neutrophils count [16] and myeloid precursors number [14], while other studies did not document effects of GH treatment on leukocytes count [10,17]. Data in children are scanty, but GH seems to have no effects on leukocytes number [10,13,[18][19][20].…”