Mast cells increase adult neural precursor proliferation and differentiation but this potential is not realized in vivo under physiological conditions

Joanna M Wasielewska,Alexander M Sykes,Tara L Walker,Anja Hoppe,Nicole Rund,Lisa Grönnert,Ruslan Rust,Axel Roers,Lukas Donix,Gerd Kempermann

doi:10.1038/s41598-017-18184-2

Abstract

There is growing evidence that both peripheral and resident immune cells play an important part in regulating adult neural stem cell proliferation and neurogenesis, although the contribution of the various immune cell types is still unclear. Mast cells, a population of immune cells known for their role in the allergic response, have been implicated in the regulation of adult hippocampal neurogenesis. Mast cell-deficient c-kitW-sh/W-sh mice have previously been shown to exhibit significantly decreased adult hippocampal neurogenesis and associated learning and memory deficits. However, given that numerous other cell types also express high levels of c-kit, the utility of these mice as a reliable model of mast cell-specific depletion is questionable. We show here, using a different model of mast cell deficiency (Mcpt5CreR26DTA/DTA), that precursor proliferation and adult neurogenesis are not influenced by mast cells in vivo. Interestingly, when applied at supraphysiological doses, mast cells can activate latent hippocampal precursor cells and increase subventricular zone precursor proliferation in vitro, an effect that can be blocked with specific histamine-receptor antagonists. Thus, we conclude that while both mast cells and their major chemical mediator histamine have the potential to affect neural precursor proliferation and neurogenesis, this is unlikely to occur under physiological conditions.

Highlights

There is growing evidence that both peripheral and resident immune cells play an important part in regulating adult neural stem cell proliferation and neurogenesis, the contribution of the various immune cell types is still unclear
C-kit is expressed by glial cells in the neocortex, hypothalamus, cerebellum and brainstem, and in nestin+ precursor cells in the SVZ18, suggesting that stem cell factor (SCF)/c-kit signaling may be involved in neuron-neuron as well as neuron-glia interactions in the mouse brain
We show that isolated peritoneal Mast cells (MC), when co-cultured at a very high density with primary adult dentate gyrus (DG) or subventricular zone (SVZ)-derived cells, can affect neural precursor proliferation and neuronal differentiation potential, an effect which is likely mediated via the release of their major chemical mediator histamine

Summary

Introduction

There is growing evidence that both peripheral and resident immune cells play an important part in regulating adult neural stem cell proliferation and neurogenesis, the contribution of the various immune cell types is still unclear. MC migrate along blood vessels of the hippocampus and fimbria and penetrate into the thalamus, where they remain throughout adulthood This may suggest an affinity of MC to populate brain regions characterized by a high degree of adaptive rewiring and structural rearrangement during life[8]. Using the MC protease (Mcpt5)CreR26DTA/DTA transgenic model, which ensures very high-specificity and high-efficiency deletion of loxP-flanked DNA in connective tissue type MC, without affecting any other cell lineages[20], we show that MC depletion does not affect neural precursor proliferation or adult neurogenesis in vivo. We show that isolated peritoneal MC, when co-cultured at a very high density with primary adult DG or SVZ-derived cells, can affect neural precursor proliferation and neuronal differentiation potential, an effect which is likely mediated via the release of their major chemical mediator histamine. Because very few MC are found within the hippocampus (and none within the SVZ), it is unlikely that such an effect would be observed in vivo, at least under physiological conditions

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