The effects of A1/A2 astrocytes on oligodendrocyte linage cells against white matter injury under prolonged cerebral hypoperfusion

Abstract

As oligodendrocyte precursor cells (OPCs) are vulnerable to ischemia, their differentiation to oligodendrocytes (OLG) is impaired in chronic cerebral hypoperfusion. Astrocyte–OLG interaction is important for white matter homeostasis. Recently, reactive astrocytes were separated into two types, A1 (cytotoxic) and A2 (neurotrophic). However, their role in prolonged cerebral hypoperfusion remains unclear. We analyzed the effects of interaction between A1–A2 astrocytes and OPC–OLG under hypoperfusion, focusing on mitochondrial migration. As an in vivo model, chronic hypoperfusion model mice were created by bilateral common carotid artery stenosis (BCAS) using microcoils. As a matching in vitro study, rat primary cells were cocultured with a nonlethal concentration of CoCl2. At 28 days after hypoperfusion, the number of OPC and astrocytes increased, whereas that of OLG decreased. Increased astrocytes were mainly A1‐like astrocytes; however, the number of A2‐like type decreased. In cell culture, OPC differentiation was interrupted under mimic chronic ischemia, but improved after astrocyte‐conditioned medium (ACM) was added. However, injured‐ACM was unable to improve OPC maturation. Incubation with CoCl2 changed astrocytes from A2‐like to A1‐like, and mitochondrial migration was also reduced. A Trkβ agonist was able to maintain astrocytes from A1‐like to A2‐like even under hyperperfused conditions, and aided in OPC maturation and memory impairment via mitochondrial migration and drug effects in cell culture study and BCAS model. The reduction of A1‐like astrocytes protects against white matter injury. Trkβ agonists may play an important role in the impairment under chronic ischemic conditions. Mitochondrial migration may be a broad therapeutic strategy for cerebrovascular diseases.Main pointsProlonged cerebral hypoperfusion leads to impaired oligodendrocyte (OLG) maturation and increased numbers of A1 astrocytes. Mitochondria migration maintained A2 astrocyte morphology, mature OLG, and myelinated white matter in vivo/vitro.

Cellular infiltration in traumatic brain injury

“…Furthermore, Ma and colleagues [ 163 ] whilst working on SAH (subarachnoid haemorrhage)-induced early brain injury added that administration of rPK2 (recombinant PK2) or augmenting PK2 expression may stimulate a modulation of astrocytic polarisation towards a more protective (A2-type) phenotype. On the other hand, Miyamoto et al [ 164 ] suggested that prolonged cerebral hypoperfusion leads to impaired oligodendrocyte maturation which, in turn, increases A1-type astrocytes number. Whilst working with the rat primary cells cocultured with a nonlethal concentration of CoCl 2 , they observed that at 28 days after hypoperfusion, the number of astrocytes increased and oligodendrocyte decreased.…”

Reduced Dendritic Spines in the Visual Cortex Contralateral to the Optic Nerve Crush Eye in Adult Mice

“… 13 – 15 Multiple studies have reported important dual roles of astrocytes in dendritic spine modulation in vitro and in vivo. 13 , 16 – 18 A1 reactive astrocytes in ischemic central nervous system diseases are induced by activated microglia, which are thought to promote the elimination of dendritic spines and the death of neurons and oligodendrocytes, 17 , 19 whereas A2 reactive astrocytes are thought to be protective. 20 The activated microglia can change their motility and phagocytic activity to eliminate dendritic spines when responding to varying light and visual stimulation.…”

A Vessel for Change: Endothelial Dysfunction in Cerebral Small Vessel Disease

“…However, Aquaporin 4 (AQP4) is located at the end-feet [120], helping to regulate cerebral water balance, normally and after traumatic brain injury at least, as AQP4KO mice survive with a better neurological outcome after this insult [121,122]. Astrocytes interact with other local cells of the unit, including oligodendroglia, with evidence that, depending on their functional state, they can promote maturation (more 'A2-like') or reduce maturation (more 'A1-like') of oligodendroglia [123] in models of chronic hypoperfusions and SVD and promote myelination and even remyelination after demyelination by their interactions [124].…”