Dr. Bo Shen’s Laboratory revealed how bone marrow peripheral nerves promote hematopoietic and vascular regeneration

On Nov 27th, Dr. Bo Shen’s Laboratory published a research paper entitled “Leptin receptor⁺ cells promote bone marrow innervation and regeneration by synthesizing nerve growth factor” in the journal Nature Cell Biology, in collaboration with Dr. Sean Morrison’s Laboratory at UT Southwestern Medical Center and Howard Hughes Medical Institute. In this article, bone marrow nerve fibers were found to be maintained by NGF synthesized by LepR⁺ cells (and their progeny) and, in turn, nerves promote hematopoietic and vascular regeneration by secreting adrenergic neurotransmitters that activate β2/β3 adrenergic receptor signaling in LepR⁺ cells.

Adult bone marrow contains peripheral nerves that promote hematopoietic regeneration after irradiation or chemotherapy (myeloablation), but little is known about the mechanism by which nerve fibers are maintained in the bone marrow or how they promote regeneration.

The researchers at Shen laboratory presented a model of bone marrow-specific denervation: they found that nerve growth factor (Ngf) was the only neurotrophic factor detected in adult bone marrow and most Ngf-expressing cells there were LepR⁺ cells. Nerve fibers were depleted within the bone marrow, but not outside of the bone marrow, in 6-month-old Lepr^cre; Ngf^fl/- mice. Therefore, NGF from LepR⁺ cells is required for bone marrow innervation. Utilizing this genetic model of bone marrow denervation, they found that bone marrow nerve fibers are dispensable for steady-state hematopoiesis.

Further investigation suggested that LepR⁺ cells, and the adipocytes they gave rise to, increased NGF production after myeloablation, promoting nerve sprouting in the bone marrow. Bone marrow nerve fibers increased the production of growth factors synthesized by LepR⁺ cells, that are critical in promoting hematopoietic and vascular regeneration. Mechanistically, bone marrow nerve fibers promote regeneration by activating b2/b3 adrenergic receptors in LepR⁺ cells, increasing the levels of these growth factors in bone marrow during regeneration.

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 (Fig. 1). Their results provide new insights in the treatment of people who receive bone marrow, or other forms of HSC, transplants.

Figure 1. Schematic illustrating a reciprocal relationship between LepR⁺ stromal cells and nerve fibers in the bone marrow.

Xiang Gao (3^rd year graduate student in Shen laboratory from the Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program) is the first author of this article. The corresponding authors are Dr. Bo Shen and Dr. Sean Morrison. Other authors of the paper include Yuehan Ni, Min Yang, Yixuan Zhang, and Jiaming Guo from Dr. Bo Shen’s Lab, and Dr. Shentong Fang from China Pharmaceutical University. The study was supported by the Natural Science Foundation of China, and National Institute of Biological Sciences, Beijing (NIBS).