Osteogenic hormones acting on the environment of the hematopoietic stem cell niche

Illing, Anett

Hematopoietic stem cells (HSCs) are the most widely studied adult stem cells in vertebrates. Despite this, little is known about the regulation of HSC maintenance in their specialized microenvironment. The aim of this thesis was to study the influence of osteogenic hormones on the regulation of HSCs. Thereby we could prove that, although estradiol increases osteoblastic cell numbers and bone mass, it does not have any advantageous effects on the endosteal HSC niche. Surprisingly, estradiol displayed alterations in the microenvironment of the vascular niche, by upregulating distinct adhesion molecules and thereby correlating with an increase of HSCs in the vascular niche. Therefore, we suggest an enhanced retention of HSCs in the vascular niche under the influence of estradiol, also proven by a decrease of HSCs in the peripheral blood. Furthermore, we investigated the effects of long-term growth hormone (GH) administration, which is known to increase bone mineral density and thereby influence the endosteal HSC microenvironment. We clearly showed increased HSC numbers in the vascular and the endosteal niche of wildtype mice after GH administration. Additionally, we proposed a Janus kinases/Signal Transducers and Activators of Transcription (Jak/STAT)-signaling-dependent mechanism of GH in the endosteal niche. To test this hypothesis, we investigated the influences of GH in a conditionally-mutated mouse model (STAT5OB), where Jak/STAT signaling is disrupted in osteoblasts by the loss of STAT5. Unexpectedly, these mice showed increased numbers of HSCs in the endosteal niche and displayed strikingly enhanced endosteal HSC numbers after GH treatment compared to wildtype controls. Loss of STAT5 in osteoblasts led to strong activation of STAT3 and, in particular, STAT1, suggesting a compensatory mechanism. We proved that Jak/STAT signaling has an important role in the endosteal HSC niche, particularly for the mediation of GH effects. The strong activation of STAT3 and STAT1 correlated with the increased numbers of HSCs in the endosteal niche.

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Illing, Anett: Osteogenic hormones acting on the environment of the hematopoietic stem cell niche. 2009.

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