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伤害感受神经调节造血干细胞动员。

Nociceptive nerves regulate haematopoietic stem cell mobilization.

机构信息

Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, New York, NY, USA.

Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA.

出版信息

Nature. 2021 Jan;589(7843):591-596. doi: 10.1038/s41586-020-03057-y. Epub 2020 Dec 23.

DOI:10.1038/s41586-020-03057-y
PMID:33361809
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7856173/
Abstract

Haematopoietic stem cells (HSCs) reside in specialized microenvironments in the bone marrow-often referred to as 'niches'-that represent complex regulatory milieux influenced by multiple cellular constituents, including nerves. Although sympathetic nerves are known to regulate the HSC niche, the contribution of nociceptive neurons in the bone marrow remains unclear. Here we show that nociceptive nerves are required for enforced HSC mobilization and that they collaborate with sympathetic nerves to maintain HSCs in the bone marrow. Nociceptor neurons drive granulocyte colony-stimulating factor (G-CSF)-induced HSC mobilization via the secretion of calcitonin gene-related peptide (CGRP). Unlike sympathetic nerves, which regulate HSCs indirectly via the niche, CGRP acts directly on HSCs via receptor activity modifying protein 1 (RAMP1) and the calcitonin receptor-like receptor (CALCRL) to promote egress by activating the Gα/adenylyl cyclase/cAMP pathway. The ingestion of food containing capsaicin-a natural component of chili peppers that can trigger the activation of nociceptive neurons-significantly enhanced HSC mobilization in mice. Targeting the nociceptive nervous system could therefore represent a strategy to improve the yield of HSCs for stem cell-based therapeutic agents.

摘要

造血干细胞（HSCs）存在于骨髓中的特殊微环境中——通常被称为“龛”-代表着受多种细胞成分影响的复杂调节环境，包括神经。尽管交感神经被认为可以调节 HSC 龛，但骨髓中的伤害感受神经元的贡献仍不清楚。在这里，我们表明伤害感受神经对于强制 HSC 动员是必需的，并且它们与交感神经合作以维持骨髓中的 HSCs。伤害感受器神经元通过分泌降钙素基因相关肽（CGRP）驱动粒细胞集落刺激因子（G-CSF）诱导的 HSC 动员。与通过龛间接调节 HSCs 的交感神经不同，CGRP 通过受体活性修饰蛋白 1（RAMP1）和降钙素受体样受体（CALCRL）直接作用于 HSCs，通过激活 Gα/腺苷酸环化酶/cAMP 途径促进迁出。摄入含有辣椒素的食物——辣椒的一种天然成分，可以触发伤害感受神经元的激活——显著增强了小鼠中的 HSC 动员。因此，靶向伤害感受神经系统可能代表一种提高基于干细胞的治疗药物中 HSC 产量的策略。

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