Early Loss of Pericytes and Perivascular Stromal Cell-Induced Scar Formation after Stroke

Abstract

Despite its limited regenerative capacity, the central nervous system (CNS) shares more repair mechanisms with peripheral tissues than previously recognized. Scar formation is a ubiquitous healing mechanism aimed at patching tissue defects via the generation of fibrous extracellular matrix (ECM). This process, orchestrated by stromal cells, can unfavorably affect the capacity of tissues to restore function. Vascular mural cells have been found to contribute to scarring after spinal cord injury. In the case of stroke, little is known about the responses of pericytes (PCs) and stromal cells. Here, we show that capillary PCs are rapidly lost after cerebral ischemia in both experimental and human stroke. Coincident with this loss is a massive proliferation of resident platelet-derived growth factor receptor beta (PDGFRb) þ and CD105 þ stromal cells, which originate from the neurovascular unit and deposit ECM in the ischemic mouse brain. The presence of PDGFRb þ stromal cells demarcates a fibrotic, contracted, and macrophage-laden lesion core from the rim of hypertrophic astroglia in both experimental and human stroke. We suggest that a previously unrecognized population of CNS-resident stromal cells drives a dynamic process of scarring after cerebral ischemia, which appears distinct from the glial scar and represents a novel target for regenerative stroke therapies.

Early Reperfusion After Brain Ischemia Has Beneficial Effects Beyond Rescuing Neurons

“…8,10 Moreover, endothelial cells were more readily detectable as a component of the microvascular structure than pericytes within infarct areas on day 1 after pMCAO ( Figure 2C), indicating that pericytes may be more vulnerable to ischemia than endothelial cells, as reported previously. 17,34 It should be kept in mind that cellular components that are potential therapeutic targets may be changing during the course of brain ischemia because of different ischemic vulnerabilities.…”

“…14 It is known that poststroke functional recovery can be brought about by the reorganization of neuronal networks in some brain areas, including in peri-infarct regions, in both animals and human, although there are some differences between them. [15][16][17] Histologically, in peri-infarct area, there is an accumulation of reactive astrocytes expressing high levels of glial fibrillary acidic protein (GFAP), forming astrogliosis in both animals and human. 17,18 It has been recently reported that poststroke astrogliosis may aid neuronal survival, 18 axonal growth, 19 and remyelination 20 in peri-infarct areas in experimental researches, although this remains controversial.…”

“…[15][16][17] Histologically, in peri-infarct area, there is an accumulation of reactive astrocytes expressing high levels of glial fibrillary acidic protein (GFAP), forming astrogliosis in both animals and human. 17,18 It has been recently reported that poststroke astrogliosis may aid neuronal survival, 18 axonal growth, 19 and remyelination 20 in peri-infarct areas in experimental researches, although this remains controversial. 21,22 Furthermore, it is experimentally suggested that efficient fibrotic formation within areas of infarct may promote peri-infarct astrogliosis.…”

Amyloid‐beta 1‐40 is associated with alterations in NG2+ pericyte population ex vivo and in vitro

“…It may thus be that the decreased activity of caspase 3/7 in response to monomer Aβ1‐40 seen in our study contributes to both the increased cell viability and the increased cell division. Finally, it is important to point out that cell cultures can never replicate a biological system and although pericyte proliferation does occur in the human brain (Fernandez‐Klett et al., 2013; Goritz et al., 2011; Matsushita et al., 2015; Paul et al., 2012), the conditions and rate in the brain are not comparable to the same in a Petri dish. Hence, we would like to stress that our cell model is useful foremost as a tool to demonstrate that differences in pericyte response to Aβ depend on both aggregation form and specie.…”

Blood–Brain Barrier Disruption, Vascular Impairment, and Ischemia/Reperfusion Damage in Diabetic Stroke

“…In DM, mitochondrial oxidative stress leads to both endothelial cell damage as well as pericyte depletion and BBB leakage 44. In the minutes to hours following ischemia, endothelial swelling and pericytes mediate capillary constriction, which is followed by rapid pericyte death leading to irreversible constriction of capillaries and BBB damage 34, 45…”