4.8 Article

Brain injury instructs bone marrow cellular lineage destination to reduce neuroinflammation

Journal

SCIENCE TRANSLATIONAL MEDICINE
Volume 13, Issue 589, Pages -

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abc7029

Keywords

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Funding

  1. National Science Foundation of China [91642205, 81830038, 81701176]
  2. Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
  3. National Key Research and Development Program of China [2018YFC1312200]

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Acute brain injury can mobilize circulating leukocytes to aggravate neural injury. This study demonstrates that bone marrow hematopoietic stem cells (HSCs) may be skewed towards the myeloid lineage in patients with intracerebral hemorrhage, leading to increased production of Ly6C(low) monocytes that suppress neuroinflammation and brain injury. The brain injury-induced modulation of HSC lineage development highlights the potential therapeutic effects of targeting bone marrow in neuroimmune interactions to reduce brain inflammation.
Acute brain injury mobilizes circulating leukocytes to transmigrate into the perivascular space and brain parenchyma. This process amplifies neural injury. Bone marrow hematopoiesis replenishes the exhausted peripheral leukocyte pools. However, it is not known whether brain injury influences the development of bone marrow lineages and how altered hematopoietic cell lineages affect neurological outcome. Here, we showed that bone marrow hematopoietic stem cells (HSCs) can be swiftly skewed toward the myeloid lineage in patients with intracerebral hemorrhage (ICH) and experimental ICH models. Lineage tracing revealed a predominantly augmented hematopoiesis of Ly6C(low) monocytes infiltrating the ICH brain, where they generated alternatively activated macrophages and suppressed neuroinflammation and brain injury. The ICH brain uses beta 3-adrenergic innervation that involves cell division cycle 42 to promote bone marrow hematopoiesis of Ly6C(low) monocytes, which could be further potentiated by the U.S. Food and Drug Administration-approved beta 3-adrenergic agonist mirabegron. Our results suggest that brain injury modulates HSC lineage development to curb distal brain inflammation, implicating the bone marrow as a unique niche for self-protective neuroimmune interaction that might be exploited to obtain therapeutic effects.

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