Dental Pulp Stem Cell-Derived Conditioned Medium Alleviates Subarachnoid Hemorrhage-Induced Microcirculation Impairment by Promoting M2 Microglia Polarization and Reducing Astrocyte Swelling

Abstract

Aneurysmal subarachnoid hemorrhage (SAH) can cause severe neurological deficits and high mortality. Early brain edema following SAH contributes to the initiation of microcirculation impairment and may further lead to delayed ischemic neurologic deficit (DIND). This study aimed to investigate whether dental pulp stem cell conditioned medium (DPSC-CM) ameliorates SAH-induced microcirculation impairment and the underlying mechanisms. SAH was induced via intrathecal injection of fresh autologous blood in Wistar male adult rat. DPSC-CM or DPSC-CM + insulin growth factor-1 (IGF-1) antibody was randomly administered by intrathecal route 5 min after SAH induction. To evaluate the underlying mechanisms of DPSC-CM in the treatment of SAH, primary rat astrocyte and microglia co-cultures were challenged with hemolysate or SAH-patient CSF in the presence or absence of DPSC-CM. The results showed that in vivo, DPSC-CM treatment decreased the brain water content, improved microcirculation impairment and enhanced functional recovery at 24 h post-SAH. DPSC-CM treatment also alleviated the expressions of water channel protein aquaporin-4 (AQP4) and pro-inflammatory cytokines, and enhanced the expressions of anti-inflammatory factors in the cortical region. However, all the beneficial effects of DPSC-CM were abrogated after treatment with IGF-1 neutralizing antibody. The in vitro results further showed that DPSC-CM treatment reduced hemolysate/SAH-patient CSF-induced astrocyte swelling and promoted M2 microglia polarization, partially through IGF-1/AKT signaling. The data suggested that DPSC-CM significantly reduced brain edema and rescued microcirculation impairment with concomitant anti-inflammatory benefits after SAH, and may potentially be developed into a novel therapeutic strategy for SAH.

Recombinant soluble form of receptor for advanced glycation end products ameliorates microcirculation impairment and neuroinflammation after subarachnoid hemorrhage

“…The rotarod test is widely used to assess motor performance in rats [ 26 ]. The test was performed as previously described [ 27 ]. Before SAH surgery, each rat was placed on the instrument (Panlab Rota Rod, Havard Apparatus) at a speed of 4 ​rpm for three consecutive days, three sessions per day for 5 ​min.…”

“…Primary astrocyte/microglia co-cultures were isolated from the cerebral cortex of 1-day-old neonatal Wistar rats as previously described [ 27 , 28 ]. Cortical tissues were collected from pups and placed in ice-cold Ca/Mg free-HBSS.…”

Functionalized Nanomaterials Capable of Crossing the Blood–Brain Barrier

“…These include pericyte degeneration or decreased pericyte coverage, basement membrane alterations, and detachment of astrocyte terminal feet from the vascular basement membrane . These astrocyte terminal podia may also exhibit a swollen phenotype under certain pathological conditions . Besides, ECs can increase the expression of leukocyte adhesion molecules, leading to increased leukocyte extravasation into the brain parenchyma under pathological conditions .…”

“…31 These astrocyte terminal podia may also exhibit a swollen phenotype under certain pathological conditions. 32 Besides, ECs can increase the expression of leukocyte adhesion molecules, leading to increased leukocyte extravasation into the brain parenchyma under pathological conditions. 33 These leukocyte−EC interactions can also directly contribute to the increased BBB permeability through the release of reactive oxygen species, cytokines, and other barrier-damaging mediators.…”

Glial cells: an important switch for the vascular function of the central nervous system

“…In the normal condition, resting microglia (M0 phenotype) function as the immune monitor in the brain; however, microglia can be activated to two polarization phenotypes, classically activated microglia (M1 phenotype promoting inflammation) and alternatively activated microglia (M2 phenotype inhibiting inflammation) in the pathological condition ( Zeng et al, 2018 ). Intriguingly, microglia polarization affects the permeability and integrity of BBB ( Yang et al, 2022 ). Pro-inflammatory microglia contribute to the high permeability of BBB, whereas anti-inflammatory cells protect BBB via the production of IL-10 and TGF-β1 ( Ronaldson and Davis, 2020 ).…”