Ο ρόλος των (BMPs) οστικών μορφογενετικών πρωτεϊνών στην αιμοποίηση

Abstract

Bone morphogenetic proteins are secreted proteins that constitute the largest subgroup within the transforming growth factor-α (TGF-α) superfamily of growth factors. BMPs were initially identified as osteoinductive growth factors that were able to induce ectopic bone and cartilage formation in skeletal muscle. However, BMPs are important for morphogenesis of the embryo and are expressed in many tissues including the hematopoietic system where they regulate their development, homeostasis, and repair. BMPs have also been implicated in various pathologic conditions such as cancer, kidney disease, arthritis and cerebrovascular disease. BMPs elicit their effects through specific serine/threonine kinase receptors and propagate the signal from cell membrane to the nucleus through Smad proteins. The interaction of BMPs with their receptors is highly regulated by secreted BMP antagonists. Previous studies have shown that BMP signaling plays a prominent role during hematopoiesis as it can adjust the development and proliferation of hematopoietic stem cells. Moreover, it has been shown by in vitro experiments that BMPs regulate the development of the thymocytes. The precise role of the BMP signaling in the development of T and B cells remains however elusive. The present doctoral thesis was focused on deciphering the in vivo functions of the BMP signaling pathway in primary lymphoid tissues. Using LacZ reporter mice the expression of several BMP/BMP antagonists was mapped in the thymus and bone marrow. Expression in the thymus was in distinct patterns both in cortical and medullary regions, as well as in stromal and haematopoietic cells, suggesting that BMP signals regulate T cell development at multiple stages. Only Bmp7 and the BMP antagonist Twisted Gastrulation (Twsg1) were also expressed in developing thymocytes. A similar picture was obtained from the analysis in the bone marrow where the strong and distinct expression of Twsg1 in different hematopoietic subsets, particular in developing B cells, was noticeable. Loss of BMP7 and TWSG1 result in embryonic or perinatal lethality, therefore these two genes were specifically ablated in the haematopoietic compartment using a conditional gene ablation approach to address their roles for the development of T and B lymphocytes in vivo. Surprisingly the absence of these two molecules from the hematopoietic compartment did not affect steady-state B and T cell development. Moreover, in order to elucidate the role of BMP signaling pathway in the steady state hematopoiesis we examined mice with conditional ablation of the type I receptor ALK2 and mice with complete ablation of the type I receptor ALK6. The conditional ablation of ALK2 from the hematopoietic cells did not result in differences in the subcellular populations of thymus and bone marrow. In contrast, loss of ALK6 resulted in a significant decrease in thymocytes, but had no effect on bone marrow cell populations. Alk6-deficient thymi showed altered stroma composition and increased apoptosis of thymocytes highlighting the importance of regulated BMP signaling for thymus homeostasis. In addition signs of blood congestion were apparent, which prompted us to investigate whether Alk6-deficiency causes a general cardiovascular defect. Histopathologic examination of aged mice revealed blood congestion in several peripheral organs, as well as an enlarged liver and spleen. Echocardiography in adult mice unveiled that Alk6 ablation leads to heart defects that affects both left and right ventricle. Cellular signs of disrupted heart function were noticed with cardiomyocyte disarray and the appearance of local fibrosis, suggesting that this pathway is essential for the normal myocardial architecture of both ventricles and thereby heart function. Collectively, the data presented in this doctoral thesis, provide new insights in the widespread involvement of BMP signaling in adult hematopoiesis and its involvement in the critically important stroma/hematopoietic cell interactions. Moreover, the studies on Alk6-deficiency illustrate the pleiotropic roles BMP signaling has for tissues homeostasis, as they reveal Alk6 involvement both in normal hematopoiesis and heart function. Latter is the first example for the importance of BMP signaling for adult heart function, which could provide new opportunities for therapeutic intervention in heart disease.