Autonomic cholinergic regulation of bone marrow stem cell niches

Resumen

Haematopoietic stem cells (HSCs) reside in specialized microenvironments in the bone marrow (BM) called “niches”. BM HSC niches comprise different stromal cell types that directly or indirectly contribute to maintain and regulate HSCs and, in turn, haematopoiesis. In the last two decades, multiple studies have revealed the importance of numerous BM stromal cell types as modulators of different HSC functions, like migration/trafficking and proliferation/quiescence. Many studies have suggested that specific niches close to the bone surface (endosteal) or around sinusoids (perisinusoidal) can regulate distinct HSC states. How these different niches cooperate to coordinate various HSC activities according to organismal demands remains unclear. In this thesis, novel neural signals have been found to regulate different HSC functions in spatially separated niches during circadian time cycles. Central cholinergic signals from the parasympathetic nervous system antagonise BM sympathetic noradrenergic activity during the nocturnal phase. Cholinergic inhibitory signals indirectly diminish 3-adrenergic signalling in perisinusoidal niches, reducing HSC egress at a specific circadian time. Cholinergic signals also appear to contribute to bone remodelling via unknown mechanisms. In addition, a specific type of sympathetic neuron that switches from noradrenergic to cholinergic fate during the first postnatal weeks has been identified in endosteal niches. Sympathetic cholinergic fibres might promote BM colonisation of HSC through Cxcl12 induction in immature BM niches. In adult mice, sympathetic cholinergic innervation targets bone-associated nestin+ BM stromal cells and promotes Cxcl12 expression, favouring HSC quiescence and long-term maintenance. In summary, neural signals from both branches of the autonomic nervous system cooperate to orchestrate and integrate different HSC features in a spatiotemporal context. While sympathetic noradrenergic signals activate HSCs and favour their trafficking, parasympathetic and sympathetic cholinergic activity promote HSC maintenance signals that counterbalance the first. This precise regulation might help to adjust stem cell functions to meet physiological requirements.