Abstract
Spinal cord injury (SCI) causes immune dysfunction, increasing the risk of infectious morbidity and mortality. Since bone marrow hematopoiesis is essential for proper immune function, we hypothesize that SCI disrupts bone marrow hematopoiesis. Indeed, SCI causes excessive proliferation of bone marrow hematopoietic stem and progenitor cells (HSPC), but these cells cannot leave the bone marrow, even after challenging the host with a potent inflammatory stimulus. Sequestration of HSPCs in bone marrow after SCI is linked to aberrant chemotactic signaling that can be reversed by post-injury injections of Plerixafor (AMD3100), a small molecule inhibitor of CXCR4. Even though Plerixafor liberates HSPCs and mature immune cells from bone marrow, competitive repopulation assays show that the intrinsic long-term functional capacity of HSPCs is still impaired in SCI mice. Together, our data suggest that SCI causes an acquired bone marrow failure syndrome that may contribute to chronic immune dysfunction.
Highlights
Spinal cord injury (SCI) causes immune dysfunction, increasing the risk of infectious morbidity and mortality
Mature immune cells develop from a pool of hematopoietic stem and progenitor cells (HSPCs) through a process known as hematopoiesis
The goal of the current study is to determine the extent of hematopoietic dysfunction after acute and chronic SCI, and to identify molecular, cellular, and physiological mechanisms that may explain any SCI-induced impairments that develop in the bone marrow
Summary
Spinal cord injury (SCI) causes immune dysfunction, increasing the risk of infectious morbidity and mortality. Data from two independent studies in which bone marrow aspirates were analyzed from small cohorts of SCI and control subjects indicate that SCI impairs human bone marrow stem cell function[21,22]. SCI increased the overall proliferation and total numbers of HSPCs in bone marrow of human SCI subjects; the ability of these stem cells to form mature immune cells was impaired[21,22]. The goal of the current study is to determine the extent of hematopoietic dysfunction after acute and chronic SCI, and to identify molecular, cellular, and physiological mechanisms that may explain any SCI-induced impairments that develop in the bone marrow. Our data show that SCI causes a rapid and chronic bone marrow failure syndrome characterized by excessive HSPC proliferation, accumulation, and impaired function. Treating bone marrow failure after SCI may help to reverse chronic immune dysfunction and anemia that persist indefinitely after SCI in humans
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