Leptin receptor+ cells promote bone marrow innervation and regeneration by synthesizing nerve growth factor

The bone marrow contains peripheral nerves that promote haematopoietic regeneration after irradiation or chemotherapy (myeloablation), but little is known about how this is regulated. Here we found that nerve growth factor (NGF) produced by leptin receptor-expressing (LepR(+)) stromal cells is required to maintain nerve fibres in adult bone marrow. In nerveless bone marrow, steady-state haematopoiesis was normal but haematopoietic and vascular regeneration were impaired after myeloablation. LepR(+) cells, and the adipocytes they gave rise to, increased NGF production after myeloablation, promoting nerve sprouting in the bone marrow and haematopoietic and vascular regeneration. Nerves promoted regeneration by activating beta 2 and beta 3 adrenergic receptor signalling in LepR(+) cells, and potentially in adipocytes, increasing their production of multiple haematopoietic and vascular regeneration growth factors. Peripheral nerves and LepR(+) cells thus promote bone marrow regeneration through a reciprocal relationship in which LepR(+) cells sustain nerves by synthesizing NGF and nerves increase regeneration by promoting the production of growth factors by LepR(+) cells.