A U.S. study has shown for the first time that enhancing signals from the nociceptive nervous system could provide new approaches to improve the collection of hematopoietic stem cells (HSCs) for treating cancers of the blood and bone marrow, the authors reported in the December 23, 2020, edition of Nature.

The findings may help cancer treatments, as "in a meaningful fraction of leukemia, multiple myeloma and lymphoma patients, particularly those who have received anticancer treatment, the HSC mobilization yield can be insufficient," said study leader Paul Frenette.

"Therefore, more efficient HSC mobilization methods would allow the harvest of sufficient HSCs for life-saving transplantation," said Frenette, a professor and director of the Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research at Albert Einstein College of Medicine in New York.

HSCs characteristically migrate to different hematopoietic sites during embryonic development and continue to be released from the adult bone marrow.

Most hematopoiesis occurs in the bone marrow, where different types of blood cells are derived from limited numbers of HSCs, which are multipotent and capable of extensive renewal.

The HSC migratory properties have facilitated their collection from the blood and transplantation as regenerative cancer treatment, although the mechanisms by which HSCs migrate out of the bone marrow remain largely unknown.

In tissues exposed to the external environment, such as the skin, lung and gut, nociceptors enable the rapid detection of external insults, including pain, cold or heat, in order to avoid organ damage.

Nociceptor sensory neurons detect these harmful stimuli and can regulate the immune response to them by releasing neurotransmitters and other regulatory molecules.

However, other than for pain perception, the role of nociceptors in a deep tissue, such as the bone marrow, is poorly understood.

In bone marrow, HSCs are found in specialized microenvironments or niches, which are complex regulatory environments influenced by multiple cellular constituents, including nerves.

Although sympathetic nerves are known to regulate the HSC niche, the role of nociceptive neurons in the bone marrow in this regard remains unclear.

"We have previously shown that nerves from the sympathetic nervous system promoted HSC mobilization in bone marrow, so we were curious to see whether nociceptive neurons might also be involved," Frenette told BioWorld Science.

In their new Nature study, the Frenette and his team showed that nociceptive neurons are required for HSC mobilization and that they interact with sympathetic nerves to maintain HSCs in the bone marrow.

Notably, nociceptor neurons were demonstrated to drive granulocyte colony-stimulating factor (G-CSF)-induced HSC mobilization via secretion of calcitonin gene-related peptide (CGRP).

"Our findings may lead to more efficient mobilization methods in [blood and bone marrow cancer] patients in whom existing methods are insufficient," Frenette said.

For example, "we have shown that the CGRP pathway synergizes with G-CSF and plerixafor [(Mozobil, Genzyme), an immunostimulant used to mobilize HSCs into the bloodstream in cancer patients]." Unlike sympathetic nerves, which regulate HSCs indirectly via the bone marrow niche, CGRP was shown to act directly on HSCs via receptor activity modifying protein 1 (RAMP1) and the calcitonin receptor-like receptor to promote HSC egress via Galphas/adenyl cyclase/cAMP signaling pathway activation.

This research identifies potential treatment targets for boosting HSC mobilization, since "we have shown that increasing the downstream signaling of the CGRP receptor RAMP1, by increasing cyclic AMP can enhance HSC mobilization," said Frenette.

Importantly, the Einstein researchers then showed that 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.

"Capsaicin tablets are currently sold over-the-counter to 'help support cardiovascular and digestive function' at higher doses than that predicted by our studies in mice for stimulating HSC mobilization in humans," said Frenette.

"These relatively low concentrations of capsaicin have biological effects without seemingly causing obvious pain," he said.

Collectively, these findings therefore suggest that targeting the nociceptive nervous system could represent a novel strategy by which to improve the yield of HSCs for stem cell-based therapies. (Gao, X. et al. Nature 2020, Advanced publication).