Postdoctoral fellow Boston Children's Hospital Boston, Massachusetts, United States
Disclosure(s):
Alec J. Walker, PhD: No financial relationships to disclose
Introduction/Rationale: The dura mater serves as a critical immunological niche for the central nervous system, yet the mechanisms governing the emergence of this niche in early life remain understudied.
Methods: Using a combination of single cell and spatial analyses, lineage tracing approaches, and genetic tools, we chart the development of the murine dural and leptomeningeal immune compartments and functionally interrogate the stromal niches that support meningeal immune cell development.
Results: In doing so, we uncover a distinctive role for the murine dura mater as a transient niche for B lymphopoiesis in the early-postnatal window. Dural B lymphopoiesis occurs as a wave spanning the first postnatal month, initiated by a shared pool of embryonic progenitors that drives a coordinated, multi-organ wave of early-life extramedullary B lymphopoiesis. B cells born during this window rapidly generate mature B cells, including a developmentally-timed contribution to the marginal zone B cell compartment. In the dura, B cells develop in defined hematopoietic foci proximal to the dural sinuses, positioned in an anatomically-restricted niche bounded by distinct fibroblast subsets composing the outer dura, inner dura, and peri-sinus dura compartments. Sinus-proximal fibroblasts intercalate into B cell foci and express the CNS stromal cell-enriched transcription factor Foxd1 and elevated levels of the pro-hematopoietic chemokine Cxcl12 in the early-life window. Ablation of Cxcl12 from Foxd1-lineage stromal cells severely impairs local B lymphopoiesis in the dura, underscoring the relevance of this unique niche for early life B cell development.
Conclusion: Together, these data reveal a critical function for dural fibroblasts in shaping the early-life B cell compartment and provide a model for how extramedullary niches may support early-life hematopoiesis. Ongoing work aims to elucidate how dural and other extramedullary niches may compensate for infection-induced loss of medullary B lymphopoiesis in the early-life window.
