Monday, March 31, 2025
3/31/2025
The Skull Bone Marrow Niche After Stroke - Outcomes and recovery after stroke are heavily influenced by the inflammation ensuing after ischemia. Among the first responders, innate immune cells are particularly numerous and inflammatory. These cells, especially neutrophils, have a life span on the order of hours and are produced and released by the hematopoietic system just-in-time. Understanding choke points for immune cell supply to ischemic brain may provide therapeutic opportunities to regulate CNS inflammation and stroke recovery. Recent work challenged the prevailing dogma that skull bone marrow is merely one among many hematopoietic sites that contributes leukocytes to the systemic circulation, from which they migrate into the ischemic brain. Rather, skull-produced cells are surprisingly frequent in the CNS. We hypothesize that skull marrow exerts a critical influence on brain health and post-stroke inflammation. This hypothesis is based on our discovery that skull hematopoietic niches are directly connected to the CNS borders via hundreds of tiny channels through the skull cortex. Skull channels transport leukocytes to meninges and, vice versa, transport CSF tracers to hematopoietic niches. In all bones, including the skull, hematopoietic stem and progenitor cells (HSPC), which give rise to leukocytes, follow the instructions of their microenvironment, that is, the hematopoietic niche they reside in. We hypothesize that in contrast to remote long bones, skull marrow niche cells, through skull channels, sample stroke-induced danger signals in the CSF. This, in turn, may have a site-specific effect on hematopoiesis, as no other marrow location is in such close contact with CSF. In this application, we propose to examine the post-stroke information transfer between the CNS and the skull marrow, which acts as a bespoke leukocyte purveyor to the CNS.
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