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

ABSTRACT: 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 β2 and β3 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.

SUBMITTER: Gao X

PROVIDER: S-EPMC10709146 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Leptin receptor<sup>+</sup> cells promote bone marrow innervation and regeneration by synthesizing nerve growth factor.

Gao Xiang X Murphy Malea M MM Peyer James G JG Ni Yuehan Y Yang Min M Zhang Yixuan Y Guo Jiaming J Kara Nergis N Embree Claire C Tasdogan Alpaslan A Ubellacker Jessalyn M JM Crane Genevieve M GM Fang Shentong S Zhao Zhiyu Z Shen Bo B Morrison Sean J SJ

Nature cell biology 20231127 12

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<sup>+</sup>) 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 myeloablat ...[more]

PMID: 38012403

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Project description:Injury or neurodegenerative disorders of the enteric nervous system (ENS) cause gastrointestinal dysfunctions for which there is no effective therapy. This study, using the benzalkonium chloride-induced rat gastric denervation model, aimed to determine whether transplantation of bone marrow-derived mesenchymal stem cells (BMSC) could promote ENS neuron regeneration and if so, to elucidate the mechanism. Fluorescently labeled BMSC, isolated from either WT (BMSC labeled with bis-benzimide [BBM]) or green fluorescent protein (GFP)-transgenic rats, were preconditioned in vitro using fetal gut culture media containing glial cell-derived neurotrophic factor (GDNF), and transplanted subserosally into the denervated area of rat pylorus. In the nerve-ablated pylorus, grafted BMSC survived and migrated from the subserosa to the submucosa 28 days after transplantation, without apparent dedifferentiation. A massive number of PGP9.5/NSE/HuC/D/Tuj1-positive (but GFP- and BBM-negative) neurons were effectively regenerated in denervated pylorus grafted with preconditioned BMSC, suggesting that they were regenerated de novo, not originating from trans-differentiation of the transplanted BMSC. BMSC transplantation restored both basal pyloric contractility and electric field stimulation-induced relaxation. High levels of GDNF were induced in both in vitro-preconditioned BMSC as well as the previously denervated pylorus after transplantation of preconditioned BMSC. Thus, a BMSC-initiated GDNF-positive feedback mechanism is suggested to promote neuron regeneration and growth. In summary, we have demonstrated that allogeneically transplanted preconditioned BMSC initiate de novo regeneration of gastric neuronal cells/structures that in turn restore gastric contractility in pylorus-denervated rats. These neuronal structures did not originate from the grafted BMSC. Our data suggest that preconditioned allogeneic BMSC may have therapeutic value in treating enteric nerve disorders.

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

Publications

Leptin receptor<sup>+</sup> cells promote bone marrow innervation and regeneration by synthesizing nerve growth factor.

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

Publications

Leptin receptor&lt;sup&gt;+&lt;/sup&gt; cells promote bone marrow innervation and regeneration by synthesizing nerve growth factor.

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OmicsDI is part of the ELIXIR infrastructure

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

Leptin receptor<sup>+</sup> cells promote bone marrow innervation and regeneration by synthesizing nerve growth factor.