Dependence on Schwann Cell-Derived Laminin-γ1 Differentiates Early Lymphoid and Myeloid Development

Blood cell production is regulated by peripheral nerve fibers that innervate the bone marrow. However, little is known about the development or maintenance of hematopoietic innervation. Schwann cells (SCs) are the primary axon 'support cells' of the peripheral nervous system (PNS), and abnormal SC development is sufficient to impair peripheral nerve function. SCs are also the primary repair cell for the PNS which makes them an attractive therapeutic target for normalization of drug or malignancy-induced 'hematopoietic neuropathy'.

We hypothesized that neural regulation of hematopoiesis is dependent on SC development. To test this hypothesis, we used the Myelin Protein Zero-Cre (MP₀-Cre); Lamc1^fl/fl mouse line in which laminin-γ1 expression is deleted from SC precursors and their progeny¹. Early SC maturation is dependent on autocrine SC precursor-derived molecules such as laminin-γ1. SC differentiation arrests prior to axon sorting and ensheathment in MP₀-Cre; Lamc1^fl/fl mice, and causes a global peripheral neuropathy that persists throughout the lifetime of the animal.

Preliminary hematopoietic analysis of 'steady state' MP₀-Cre; Lamc1^fl/fl and littermate control mice has shown the following: (1) MP₀-Cre; Lamc1^fl/fl bone marrow is innervated, and Cre-mediated gene recombination occurs in cells immunophenotypically consistent with SCs throughout the peripheral nervous system, including those in the bone marrow; (2) MP₀-Cre; Lamc1^fl/fl mice are lymphopenic but not neutropenic; (3) MP₀-Cre; Lamc1^fl/fl mice have significantly reduced spleen size and cellularity; and (4) MP₀-Cre; Lamc1^fl/fl bone marrow has an ~50% reduction in Lin^-Sca-1⁺Kit⁺(LSK) cells (measured as a percentage of the Lin^- compartment of the bone marrow). These results are consistent with earlier work by our groups in which we found that global Lamc1 gene deletion in adult mice induced peripheral blood lymphopenia, reduced spleen size, and a niche-dependent reduction of lymphoid progenitor and precursor cells that was secondary to increased lymphoid precursor cell apoptosis and reduced proliferation (UBC-Cre^ERT2; Lamc1^fl/fl mouse line). As with the SC-specific laminin-γ1 deficient mice, myelopoiesis was preserved in the UBC-Cre^ERT2; Lamc1^fl/fl mice.

Based on results from MP₀-Cre; Lamc1^fl/fl and UBC-Cre^ERT2; Lamc1^fl/fl mice, we conclude that early lymphoid but not myeloid development requires laminin-γ1 expression by MP₀-Cre-targetted niche cells, i.e. Schwann Cells. Our results are consistent with reports from other labs that hematopoietic sympathetic neuropathy promotes aberrant myeloid expansion at the expense of lymphopoiesis². Going forward, we will determine whether lymphopoietic development is dependent on global versus laminin-specific SC-derived cues, and whether these signals are transmitted directly between SCs and lymphoid biased HSPCs or indirectly via other components of the hematopoietic niche. We anticipate that this line of investigation will provide molecular insights and pharmacologic targets for prevention and or normalization of the 'hematopoietic neuropathy' induced by diabetes, aging, neurotoxic chemotherapies and myeloid malignancies.

REFERENCES:

1 Yu, W. M., Feltri, M. L., Wrabetz, L., Strickland, S. & Chen, Z. L. Schwann cell-specific ablation of laminin gamma1 causes apoptosis and prevents proliferation. J Neurosci25, 4463-4472, doi:10.1523/JNEUROSCI.5032-04.2005 (2005).

2 Maryanovich, M. et al. Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche. Nat Med24, 782-791, doi:10.1038/s41591-018-0030-x (2018).