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1847 Dependence on Schwann Cell-Derived Laminin-γ1 Differentiates Early Lymphoid and Myeloid Development

Program: Oral and Poster Abstracts
Session: 506. Hematopoiesis and Stem Cells: Microenvironment, Cell Adhesion, and Stromal Stem Cells: Poster II
Hematology Disease Topics & Pathways:
Biological Processes, white blood cells, Cell Lineage, hematopoiesis, microenvironment
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Kristin Komnick, MPH1*, Jennifer May1*, Pouneh Kermani, PhD2*, Sreemanti Basu, PhD1*, Irene Hernandez1*, Mark Zogg, BS1*, British L Fields1,3*, Joshua Morris, MD1,3*, Hartmut Weiler, PhD1 and Karen-Sue Carlson, MD, PhD1,4

1Blood Research Institute, Versiti, Milwaukee, WI
2Department of Hematology and Oncology, Weill Cornell Medicine, New York, NY
3Medical College of Wisconsin, Milwaukee, WI
4Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI

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); Lamc1fl/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; Lamc1fl/fl mice, and causes a global peripheral neuropathy that persists throughout the lifetime of the animal.

Preliminary hematopoietic analysis of ‘steady state’ MP0-Cre; Lamc1fl/fl and littermate control mice has shown the following: (1) MP0-Cre; Lamc1fl/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; Lamc1fl/fl mice are lymphopenic but not neutropenic; (3) MP0-Cre; Lamc1fl/fl mice have significantly reduced spleen size and cellularity; and (4) MP0-Cre; Lamc1fl/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-CreERT2; Lamc1fl/fl mouse line). As with the SC-specific laminin-γ1 deficient mice, myelopoiesis was preserved in the UBC-CreERT2; Lamc1fl/fl mice.

Based on results from MP0-Cre; Lamc1fl/fl and UBC-CreERT2; Lamc1fl/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.


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 Neurosci 25, 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 Med 24, 782-791, doi:10.1038/s41591-018-0030-x (2018).

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH