Nociceptive nerves regulate haematopoietic stem cell mobilization.

Abstract

Haematopoietic stem cells (HSCs) reside in specialized microenvironments in the bone marrow (BM), often referred to as “niches”, which represent complex regulatory milieux influenced by multiple cellular constituents, including nerves1,2. Although sympathetic nerves regulate the HSC niche3-6, the contribution of nociceptive neurons in the BM remains unclear. Here we show that nociceptive nerves are required for enforced HSC mobilization and collaborate with sympathetic nerves for HSC maintenance in BM. 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 niche3,4,6, CGRP acts directly on HSCs via the receptor activity modifying protein-1 (RAMP1) and calcitonin-receptor-like receptor (CALCRL), to promote egress by activating Gαs/Adenylyl cyclase/cAMP pathway. Remarkably, the ingestion of food containing capsaicin (a natural component of chili peppers), significantly enhanced HSC mobilization. Thus, targeting the nociceptive nervous system is a novel strategy to improve the HSC yield for stem cell-based therapeutics.