Mechanism of White Matter Injury and Promising Therapeutic Strategies of MSCs After Intracerebral Hemorrhage

Abstract

Intracerebral hemorrhage (ICH) is the most fatal subtype of stroke with high disability and high mortality rates, and there is no effective treatment. The predilection site of ICH is in the area of the basal ganglia and internal capsule (IC), where exist abundant white matter (WM) fiber tracts, such as the corticospinal tract (CST) in the IC. Proximal or distal white matter injury (WMI) caused by intracerebral parenchymal hemorrhage is closely associated with poor prognosis after ICH, especially motor and sensory dysfunction. The pathophysiological mechanisms involved in WMI are quite complex and still far from clear. In recent years, the neuroprotection and repairment capacity of mesenchymal stem cells (MSCs) has been widely investigated after ICH. MSCs exert many unique biological effects, including self-recovery by producing growth factors and cytokines, regenerative repair, immunomodulation, and neuroprotection against oxidative stress, providing a promising cellular therapeutic approach for the treatment of WMI. Taken together, our goal is to discuss the characteristics of WMI following ICH, including the mechanism and potential promising therapeutic targets of MSCs, aiming at providing new clues for future therapeutic strategies.

Cerebral Hemorrhage: Pathophysiology, Treatment, and Future Directions

“…It is hypothesized neurogenesis and repair occurs following ICH, as several preclinical studies have shown improvement in rodent models of ICH when animals are treated with neural, adiposederived, or mesenchymal stem cells. [341][342][343][344] Whether neural stem cells differentiate into functional neurons or enhance recovery through effects on the tissue milieu remains uncertain. A gap remains in the ability to longitudinally quantify reparative processes using noninvasive advanced neuroimaging, particularly in patients.…”

Mesenchymal Stem Cell Application and Its Therapeutic Mechanisms in Intracerebral Hemorrhage

“…Some studies have verified that MSCs can be isolated from various adult tissues such as the bone marrow, adipose tissue, synovium, and neonatal tissues, including the umbilical cord (blood), placenta, amniotic fluid, and amniotic membrane, and possess the potential of differentiating into diverse cell lineages and tissues like bone, adipose tissue, cartilage, nerves, and liver, both in vivo and in vitro ( Gao et al, 2018 ; Sumer et al, 2018 ; Mathot et al, 2019 ; Gong et al, 2021 ; Li J. et al, 2021 ; Li Q. Y. et al, 2021 ; Ramesh et al, 2021 ; Souza et al, 2021 ; Zhu et al, 2021 ; Bian et al, 2022 ). Others have verified that MSC treatment holding promise exerts indirect therapeutic mechanisms such as anti-inflammation ( Huang et al, 2019 ), secretion of growth factors ( Tang W. et al, 2021 ; Ulpiano et al, 2021 ), and EVs ( Bang and Kim, 2022 ), which are associated with the recovery of damaged tissues.…”

Intracerebral Hemorrhage: The Effects of Aging on Brain Injury

“…White matter injury is observed in both acute and chronic phases of ICH and is characterized by demyelination, axonal damage and oligodendrocyte death ( Ni et al, 2015 ). Though the precise mechanism of white matter injury after ICH is enigmatic, iron-induced oxidative stress could culminate in white matter damage ( Li et al, 2021 ). In a rat model of ICH, white matter injury correlated with brain edema and poor neurological outcomes ( Tao et al, 2016 ).…”

“…In a rat model of ICH, white matter injury correlated with brain edema and poor neurological outcomes ( Tao et al, 2016 ). Moreover, white matter injury is a major cause of sensory-motor deficits commonly seen in ICH patients ( Li et al, 2021 ) and was associated with cognitive impairment ( Smith et al, 2004 ). Of note, aging is often associated with cerebral white matter lesions characterized by demyelination, gliosis, and capillary degeneration ( Hoffman et al, 1985 ; Baltan et al, 2008 ; Asdaghi et al, 2012 ).…”