Non–cell-autonomous hedgehog signaling promotes murine B lymphopoiesis from hematopoietic progenitors

Abstract

The role of hedgehog (Hh) signaling in B lymphopoiesis has remained unclear. We observed that the proliferation of pro-B cells in stromal cocultures was impaired by interruption of Hh signaling, prompting us to investigate whether the target of Hh antagonism was intrinsic or extrinsic to the B-lymphoid compartment. In the present study, using conditional deletion of the pathway activator gene Smo, we found that cell-autonomous Hh signaling is dispensable for B-cell development, B-lymphoid repopulation of the BM, and humoral immune function. In contrast, depletion of the Smo protein from stromal cells was associated with impaired generation of B-lymphoid cells from hematopoietic stem progenitor cells, whereas reciprocal removal of Smo from these cells had no effect on the production of B-cell progenitors. Depletion of Smo from stromal cells was associated with coordinate down-regulation of genes for which expression is associated with osteoblastoid identity and Blymphopoietic activity. The results of the present study suggest that activity of the Hh pathway within stromal cells promotes B lymphopoiesis in a non-cellautonomous fashion. (Blood. 2012; 119(23):5438-5448) IntroductionThe major pathway of B lymphopoiesis from hematopoietic stem progenitor cells has been described in some detail previously. 1 The earliest identifiable B-cell progenitors, termed pro-B cells, arise initially in the fetal liver and subsequently in the BM, carrying partial D-to-J H rearrangements of both Ig alleles. Subsequent, productive V H -to-DJ H joining triggers the transition to the pre-B stage, at which time the Ig heavy chain associates with surrogate light chains to form the pre-BCR. Signals emanating from the pre-BCR suppress further heavy-chain rearrangement, activate Ig light-chain rearrangement, promote proliferation, inhibit apoptosis, and increase sensitivity to IL-7. After productive Ig light-chain rearrangement, counterselection of self-reactive specificities, and receptor editing, nascent B cells leave the marrow for peripheral lymphoid tissues.In the BM, B-cell development occurs in essential association with stromal cells. 2 Some effects of stromal cells on B-cell development are mediated by direct contact, such as the interaction of c-Kit on pro-B cells with SCF on stromal cells. 3 Other effects are mediated by soluble products of stromal cells, such as IL-7, which supports maturation beyond the pro-B stage. 4 However, the contributions of the stromal environment to B-lymphoid differentiation remain poorly defined, as evident from the requirement for stromal cells in addition to soluble factors in systems that support B lymphopoiesis ex vivo.The Hedgehog (Hh) signaling pathway serves several developmental functions, including establishment of tissue polarity, embryonic patterning, and stem cell maintenance. 5 Hh signaling is initiated by a family of ligands that includes Sonic Hh (Shh), Indian Hh (Ihh), and Desert Hh (Dhh). In the absence of ligand, the receptor Patched (Ptch) inhibits the activator Smoothened (Smo); t...

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