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Reciprocal Interaction Between Pericytes and Macrophage in Poststroke Tissue Repair and Functional Recovery
Tomoya Shibahara1, Tetsuro Ago1, Masaki Tachibana1
1Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Japan.
Background And Purpose:
Poststroke tissue repair, comprised of macrophage-mediated clearance of myelin debris and pericyte-mediated fibrotic response within the infarct area, is an important process for functional recovery. Herein, we investigated the reciprocal interaction between pericytes and macrophages during poststroke repair and functional recovery.
Methods:
We performed a permanent middle cerebral artery occlusion in both wild-type and pericyte-deficient PDGFRβ (platelet-derived growth factor receptor β) heterozygous knockout (Pdgfrb+/-) mice and compared histological changes and neurological functions between the 2 groups. We also examined the effects of conditioned medium harvested from cultured pericytes, or bone marrow-derived macrophages, on the functions of other cell types.
Results:
Localization of PDGFRβ-positive pericytes and F4/80-positive macrophages was temporally and spatially very similar following permanent middle cerebral artery occlusion. Intrainfarct accumulation of macrophages was significantly attenuated in Pdgfrb+/- mice. Intrainfarct pericytes expressed CCL2 (C-C motif ligand 2) and CSF1 (colony stimulating factor 1), both of which were significantly lower in Pdgfrb+/- mice. Cultured pericytes expressed Ccl2 and Csf1, both of which were significantly increased by PDGF-BB and suppressed by a PDGFRβ inhibitor. Pericyte conditioned medium significantly enhanced migration and proliferation of bone marrow-derived macrophages. Poststroke clearance of myelin debris was significantly attenuated in Pdgfrb+/- mice. Pericyte conditioned medium promoted phagocytic activity in bone marrow-derived macrophages, also enhancing both STAT3 (signal transducer and activator of transcription 3) phosphorylation and expression of scavenger receptors, Msr1 and Lrp1. Macrophages processing myelin debris produced trophic factors, enhancing PDGFRβ signaling in pericytes leading to the production of ECM (extracellular matrix) proteins and oligodendrogenesis. Functional recovery was significantly attenuated in Pdgfrb+/- mice, parallel with the extent of tissue repair.
Conclusions:
A reciprocal interaction between pericytes and macrophages is important for poststroke tissue repair and functional recovery.
Insights
Pericytes and macrophages interact to repair brain tissue after stroke. This interaction is crucial for clearing debris and promoting functional recovery, with impaired communication leading to worse outcomes.
Area of Science:
- Neuroscience
- Immunology
- Regenerative Medicine
Background:
- Poststroke tissue repair involves macrophages clearing debris and pericytes mediating fibrosis.
- Understanding the interplay between these cells is vital for improving functional recovery after stroke.
Purpose of the Study:
- To investigate the reciprocal interaction between pericytes and macrophages during poststroke repair.
- To elucidate the role of this interaction in functional recovery following ischemic stroke.
Main Methods:
- Used permanent middle cerebral artery occlusion in wild-type and pericyte-deficient PDGFRβ heterozygous knockout mice.
- Analyzed histological changes, neurological functions, and cell-cell communication using conditioned media.
Main Results:
- Pericyte deficiency (PDGFRβ+/- mice) reduced macrophage infiltration and myelin debris clearance.
- Pericytes secrete CCL2 and CSF1, enhancing macrophage migration, proliferation, and phagocytosis.
- Macrophages promote pericyte function and extracellular matrix production, supporting oligodendrogenesis.
Conclusions:
- A reciprocal interaction between pericytes and macrophages is essential for effective poststroke tissue repair.
- This cellular crosstalk significantly influences functional recovery after stroke.
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