Compartmentalization of bone morphogenetic proteins and their antagonists in lymphoid progenitors and supporting microenvironments and functional implications

Abstract

SummaryBone morphogenetic protein (BMP) signalling regulates lymphopoiesis in bone marrow and thymus via the interaction of haemato-lymphoid progenitors with the stroma microenvironment. Despite increasing functional evidence for the role of BMP signalling in lymphopoiesis, little is known of the spatial distribution of BMP/BMP antagonists in the thymus and of how BMP signals exert specific functions in developing lymphocytes. We analysed expression of BMP/BMP antagonists in the thymus and bone marrow and determined the topology of BMP/BMP antagonist expression using lacZ reporter mice. Bmp4, Bmp7, Gremlin and Twisted gastrulation (Twsg1) are all expressed in the thymus and expression was clearly different for each gene investigated. Expression was seen both in cortical and medullary regions suggesting that BMP signals regulate all stages of T-cell development. Two genes in particular, Bmp7 and Twsg1, were dynamically expressed in developing T and B lymphocytes. Their conditional ablation in all haematopoietic cells surprisingly did not affect the steady state of B-cell and T-cell development. This indicates that both lymphoid cellderived BMP7 and TWSG1 are dispensable for normal lymphopoiesis and that bone-marrow stroma-derived TWSG1 is responsible for the lymphoid defects observed in Twsg1 null mice. In summary our data demonstrate a complex network of lymphoid and stroma derived BMP signals involved in the orchestration of lymphopoiesis in both bone marrow and thymus.

Bone Marrow Microenvironment Niche Regulates miR-221/222 in Acute Lymphoblastic Leukemia

“…Healthy pro-B cells rely on the bone marrow’s signaling cues for survival, growth and differentiation (35) to sustain one lineage of baseline hematopoiesis. In the setting of ALL these interactions are “hijacked” and provide a sanctuary site for malignant B lineage cells that share many characteristics with their normal counterparts.…”

Autosomal dominant mesomandibular fibro-osseous dysplasia: a self-resolving inherited fibro-osseous lesion of the jaws

“…BMPs regulate a number of cellular processes, including proliferation, differentiation, migration, apoptosis, and epithelial-mesenchymal interactions (Hallahan et al, 2003; von der Hardt et al, 2007; Wagner et al, 2010). Postnatally, BMPs play a role in regulating tissue homeostasis in physiological and pathological conditions, such as tissue regeneration (Simic and Vukicevic, 2007; Larman et al, 2009), bone remodeling (Pham et al, 2011), immune function (Passa et al, 2011; Tsalavos et al, 2011), and cancer (Thawani et al, 2010; Buijs et al, 2012). …”

A Tale from TGF-β Superfamily for Thymus Ontogeny and Function

“…In addition, apoptosis-driven production of TGF-β signals resulted in an increased generation of thymic regulatory T (tTreg) cells (see below) ( 80 ). Interestingly, mTECs are the cell type in the thymus that express most ligand genes of the TGF-β superfamily and their cognate receptors – Inha and Inhbb , Bmp2 , Bmp3 , Bmp4 , Bmp5 , Bmp6 , and Gdf6 / Bmp13 , Gdf3 , Gdf6 / Bmp13 , Gdf8 / myostatin , Gdf10 , Gdf11 , and Gdf15 , Lefty1 and Lefty2 , Tgfb1 , Tgfb2 , and Tgfb3 along with Acvr2a (ActRII), and Acvr2b (ActRIIB), Acvr1 (Alk2), Bmpr1a (Alk3), and Bmpr2 (BMPRII) for BMP/growth and differentiation factor (GDF) signaling, and Acvr1b (Alk4) and Tgfbr1 (Alk5) for the TGF-β/Activin/Nodal pathway, in addition to the type III receptor gene Tdgf1 (Cripto) ( 71 , 72 , 81 , 82 ).…”

“…Thymocytes express no Bmpr1b (Alk6), Acvr1 (Alk2), and Acvr1c (Alk7) during thymopoiesis ( 127 , 129 ). Yet, high levels of inhibin βA subunit ( Inhba ) and TGF-β1 ( Tgfb1 ) contrast with reduced levels of the inhibin α subunit ( Inha ), Bmp2, Bmp4, and Bmp7 at the DN2 stage ( 81 , 82 , 127 , 130 ). When Inha mutants were used for E14.0 FTOC, a partial arrest at the DN2 stage impaired further T cell maturation ( 148 ).…”

“…Following T cell differentiation into CD44 −/low CD25 + DN3 cells, V β to DJ β recombination gives rise to the β chain of the pre-TCR ( 143 ). At this stage, the levels of Inha , Bmp2 , and Bmp4 remain relatively low, Bmp7 becomes upregulated up to the CD3 − CD8 + intermediate single-positive (ISP) stage, and expression of Inhba and Tgfb1 declines ( 82 , 127 , 130 ). Levels of Alk4 ( Acvr1c ), Alk5 ( Tgfbr1 ), and ActRII ( Acvr2a ) gradually reduce as thymocytes mature, in contrast to TβRII, which is slowly upregulated – at this stage, Alk4 and Alk5 are co-expressed ( 134 ).…”