Biology subjects

Kigerl, K. A.

Publications and source records attributed to Kigerl, K. A..

3 recordsLinked to original sources

bioRxiv2025

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

Spinal cord injury (SCI) triggers systemic pathology beyond the nervous system, including bone marrow failure that can worsen infection risk, anemia, and motor recovery. Here we identify a neuroendocrine mechanism that rapidly imprints long-lasting dysfunction in hematopoietic stem cells (HSCs), which sustain lifelong production of immune cells, red blood cells, and platelets. Rather than mounting a canonical stress-hematopoietic response, SCI HSCs enter a broadly repressed state marked by chromatin closure and suppression of programs required for cell-cycle entry, genome maintenance, and redox defense. This maladaptive state leads to persistent DNA damage, impaired oxidative stress resolution, pancytopenia, and loss of long-term HSC regenerative capacity. Mechanistically, SCI-induced glucocorticoid surges drive glucocorticoid receptor-dependent repression of DNA repair genes, including Lig1 and Fen1. Acute glucocorticoid receptor blockade after SCI restores durable hematopoiesis, revealing an early therapeutic window to preserve hematopoietic integrity after neurotrauma. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/680535v2_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1627bb3org.highwire.dtl.DTLVardef@a73e19org.highwire.dtl.DTLVardef@1ddf85dorg.highwire.dtl.DTLVardef@1dcd8fe_HPS_FORMAT_FIGEXP M_FIG C_FIG Key FindingsO_LIAcute SCI prevents induction of normal stress-induced repair programs in HSCs. C_LIO_LISCI HSPCs exhibit increased chromatin compaction. C_LIO_LISCI compromises HSC genome-maintenance and redox capabilities. C_LIO_LISCI HSCs have defects in normal cell cycle regulation, are hypersensitive to genotoxic stress, and are deficient in long-term reconstitution. C_LIO_LIEarly glucocorticoid receptor (GR) blockade restores long-term hematopoiesis, supporting a GR-dependent but reversible repression mechanism. C_LI

cell biology↗

bioRxiv2025

Precision Prediction of Microbial Ecosystem Impact on Host Metabolism Using Genome-Resolved Metagenomics

Microorganisms often drive ecosystem function, yet precision disturbance response and ecosystem impact predictions remain challenging due to poorly captured ecological and metabolic interconnectedness and functional redundancy. For example, while mammalian gut dysbiosis is recognized to influence host metabolism, key microbiota and mechanisms governing their effects remain poorly understood. Here we developed a genome-resolved eco-systems biology workflow to predict how gut microbial metabolism affects mammalian health, and we applied it to a spinal cord-gut axis dataset. By scaling and integrating temporally resolved network analytics and consensus statistical approaches, we identified largely previously uncharacterized microbial species that best predict host physiology following neurological impairment. In silico validation through "complete" pathway-centric and comparative genomic analyses revealed that among these species, the major encoded microbial metabolic changes were in pathways directly linked to host nitrogen balance, and they varied by host sex and microbial ecotype/species. Moreover, we identified the exact bacterial species (and their draft genome sequences) driving urease-dependent versus amino acid-dependent nitrogen gut metabolism - findings that explain previously mechanistically-ambiguous, but clinically relevant, ammonia-driven host nitrogen imbalance. More broadly, these ecology- and community-aware approaches provide a framework to study dynamic, interconnected microbiomes that advances from enrichment-based single-taxon and single-gene correlations towards building microbe(s)-driven mechanistic insights that integrate community context and whole pathways.

microbiology↗

bioRxiv2023

Targeting the Microbiome to Improve Gut Health and Breathing Function After Spinal Cord Injury

Spinal cord injury (SCI) is a devastating condition characterized by impaired motor and sensory function, as well as internal organ pathology and dysfunction. This internal organ dysfunction, particularly gastrointestinal (GI) complications, and neurogenic bowel, can reduce the quality of life of individuals with an SCI and potentially hinder their recovery. The gut microbiome impacts various central nervous system functions and has been linked to a number of health and disease states. An imbalance of the gut microbiome, i.e., gut dysbiosis, contributes to neurological disease and may influence recovery and repair processes after SCI. Here we examine the impact of high cervical SCI on the gut microbiome and find that transient gut dysbiosis with persistent gut pathology develops after SCI. Importantly, probiotic treatment improves gut health and respiratory motor function measured through whole-body plethysmography. Concurrent with these improvements was a systemic decrease in the cytokine tumor necrosis factor-alpha and an increase in neurite sprouting and regenerative potential of neurons. Collectively, these data reveal the gut microbiome as an important therapeutic target to improve visceral organ health and respiratory motor recovery after SCI. Research HighlightsO_LICervical spinal cord injury (SCI) causes transient gut dysbiosis and persistent gastrointestinal (GI) pathology. C_LIO_LITreatment with probiotics after SCI leads to a healthier GI tract and improved respiratory motor recovery. C_LIO_LIProbiotic treatment decreases systemic tumor necrosis factor-alpha and increases the potential for sprouting and regeneration of neurons after SCI. C_LIO_LIThe gut microbiome is a valid target to improve motor function and secondary visceral health after SCI. C_LI

neuroscience↗