Transcriptional and epigenetic repression of hematopoietic stem cells underlies bone marrow failure after spinal cord injury

Spinal cord injury (SCI) exerts profound systemic effects that extend beyond the nervous system, including the onset of bone marrow failure. Here, we show that SCI impairs the ability of hematopoietic stem cells (HSCs) to exit quiescence, proliferate, and differentiate, ultimately compromising long-term hematopoiesis. Using in-vivo transplantation assays, single-cell transcriptomics, and chromatin accessibility profiling, we show that SCI suppresses canonical stress-induced transcriptional programs in HSCs, including those governing cell cycle progression and DNA repair. These transcriptional changes are accompanied by epigenetic remodeling, with reduced chromatin accessibility at key genomic loci required for genome maintenance. Functionally, SCI HSCs exhibit impaired proliferation, persistent DNA damage, and an inability to resolve oxidative stress, even in the absence of ongoing injury. These defects culminate in bone marrow failure and pancytopenia in recipient mice. Our findings reveal a previously unrecognized systemic consequence of SCI and underscore the need for therapeutic strategies to preserve hematopoietic integrity following SCI.