Spinal cord injury causes chronic bone marrow failure

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.

Peripheral Immune Dysfunction: A Problem of Central Importance after Spinal Cord Injury

“…Just how exactly bone marrow-derived immunity changes after SCI has been described in a few publications [ 86 , 87 , 88 ]. Clinically, persons with SCI exhibit impaired bone marrow stem cell function [ 86 , 87 ].…”

“…When bone marrow aspirates were cultured, the number of long-term culture-initiating cells was significantly reduced in cultures from SCI persons, particularly tetraplegics, indicative of decreased progenitor growth [ 86 ]. Preclinically, a recent publication explored the mechanisms behind SCI-induced bone marrow hematopoietic dysfunction [ 88 ]. After SCI, mice exhibited increased hematopoietic stem cell proliferation and accumulation in the bone marrow, as well as impaired mobilization regardless of injury level and severity ( Figure 2 ).…”

“…In T3-transected mice specifically, expression of bone marrow cytokines and chemokines was significantly increased, and C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C motif chemokine receptor 4 (CXCR4) signaling specifically led to sequestration of hematopoietic stem cells and mature B cells. These changes appear to have functional implications, as the bone marrow response to inflammatory stimulation with lipopolysaccharide (LPS) was impaired after SCI [ 88 ].…”

Single Cell Profiling of CD45+ Spinal Cord Cells Reveals Microglial and B Cell Heterogeneity and Crosstalk Following Spinal Cord Injury

“…The mechanism leading to B cell invasion into the spinal cord following SCI is currently unknown, although we show chemokine signaling may be involved. Intriguingly, other studies have shown lymphopoiesis is impaired in the bone marrow following SCI and B cells fail to mobilize 65 , suggesting B cells observed in the injured spinal cord might have a different origin. Indeed, recent studies suggest the meninges, cerebrospinal fluid, and vertebral bone may be a source of B cells entering the injured CNS [66][67][68][69] .…”

Reduction of Cell Proliferation by Acute C2H6O Exposure

“…In particular, in MITO-Luc mice, high luciferase activity can be detected in spleen, testis, and bone marrow (vertebral column, sternum, femur), while non-proliferating tissues, such as lung, brain, heart, aorta, skeletal muscle, liver, and kidney, do not emit light under physiological conditions [ 27 ]. This experimental model has been instrumental in studies analyzing cell proliferation in response to hyperbilirubinemia [ 28 ], toxic insult [ 29 ], and ischemic [ 30 ] and spinal cord [ 31 ] injuries.…”