Chinese neuroscientists have identified a bone marrow (BM) response to acute brain injury, in which the fate and function of BM hematopoietic cells are shaped by brain injury, suggesting that the brain can mobilize a population of protective monocytes and direct them to the injury site.
This mechanism's recognition could pave the way to developing protective brain therapies by harnessing beneficial BM hematopoiesis for acute neurological insults such as intracerebral hemorrhage (ICH), the authors reported in the April 14, 2021, edition of Science Translational Medicine.
The BM offers a unique niche for neuroimmune interactions in health and disease, as the intersection of the CNS, peripheral immune system, and the site of leukocyte production.
ICH is a major acute brain injury causing both primary injury due to mechanical hematoma and secondary injury driven by perihematomal edema (PHE) development, but has no approved treatments, besides craniotomy in severe cases.
"The effectiveness of pharmacological interventions, including hyperosmolar therapy and iron chelation, is either uncertain or awaits further investigation in ICH patients," said study leader Qiang Liu, a professor of neurology at Tianjin Medical University General Hospital.
"Emergency craniotomy is necessary for some ICH patients as a life-saving procedure," Liu told BioWorld Science.
"However, clinical trials of targeting ICH hematoma by surgical resection or... clot aspiration with tissue plasminogen activator have not shown therapeutic efficacy, with ICH remaining the least treatable form of stroke."
Inflammation is a major contributor to secondary brain injury driving PHE expansion, blood-brain barrier (BBB) disruption, and neurological deterioration after ICH, with circulating myeloid monocyte numbers increasing markedly after ICH.
Among brain parenchyma-infiltrating immune cells, monocytes reach the CNS within hours of ICH, peak days after the initial assault, and then outnumber other immune cell subtypes.
Due to their short lifespan, monocytes have a rapid turnover, rapidly exhausting blood and cell reserves after ICH. However, sources of new monocytes after ICH and their influence on newly generated monocytes in acute injury remain unclear.
ICH activates adrenergic innervation, inducing lymphocyte hypofunction and lymphopenia. Unlike the reduced numbers of blood lymphocytes, the surge of circulating monocytes after ICH implies involvement of a continuous supply of monocytes from BM, raising several key questions.
For example, what is the precise effect of ICH on BM hematopoietic cells, given that BM is an immune organ and the primary site for hematopoiesis, and what neurogenic signaling mediates cross-talk between injured brain and BM?
Moreover, because hematopoiesis is tightly regulated by hematopoietic stem cells (HSCs), with an output of balanced leukocyte subtypes, which key molecular mechanism controls the HSC response to ICH?
Finally, what happens to newly produced immune cells like monocytes derived from BM and what is the impact of new monocytes on neuroinflammation and neural injury?
These questions were addressed in the new Science Translational Medicine study, which showed that BM HSCs were swiftly skewed toward the myeloid lineage, both in ICH patients and in experimental ICH models.
"Within 24 hours of ICH onset, BM HSCs were found to be significantly skewed toward the myeloid cell lineage in patients and in two ICH mouse models induced by injection of autologous blood or by collagenase injection," said Liu.
"This myeloid bias of HSCs was demonstrated by increased numbers of BM myeloid cell progenitors, as measured by flow cytometric analysis," he explained.
Lineage tracing then revealed a significantly augmented hematopoiesis of Ly6Clow monocytes that subsequently infiltrated the ICH brain, where they generated macrophages and suppressed inflammation and brain injury.
"Ly6low monocytes are regulatory monocytes that can reduce BBB disruption, leukocyte infiltration and brain edema," Liu said.
ICH brains signaled via beta3adrenergic innervation to promote BM hematopoiesis of Ly6Clow monocytes, which could be further potentiated using the beta3adrenergic agonist mirabegron.
"The use of the beta3 agonist led to increased BM production of regulatory monocytes, reduced brain edema and improved neurological outcomes in ICH mouse models, although this awaits future investigation in clinical trials," said Liu.
"This is a key finding, because it provides a new pharmacological approach that has potential as a treatment option for ICH, while mirabegron has been FDA-approved with reasonable safety."
Together, these results suggest that brain injury modulates HSC lineage development to limit distal brain inflammation, implicating BM as a site of selfprotective neuroimmune interaction, which might be exploited therapeutically.
"We have found that BM, as an immune organ and hematopoietic system, can swiftly respond to ICH and curb neuroinflammation by producing regulatory immune cells," concluded Liu.
"These findings suggest that BM may serve as a treatment target to restrict harmful neuroinflammation after brain injury and, although this study is focused on ICH, these findings may be extended to other types of brain damage such as traumatic brain injury," he said.
"In future, we plan to perform early-phase clinical trials of improving neurological outcomes in ICH patients by modulating the BM response and we hope to study the role of BM hematopoietic system in other types of brain damage."