Genetic conversion of proliferative astroglia into neurons after cerebral ischemia: a new therapeutic tool for the aged brain?

Abstract

Ischemic stroke represents the 2nd leading cause of death worldwide and the leading cause for long-term disabilities, for which no cure exists. After stroke, neurons are frequently lost in the infarct core. On the other hand, other cells such as astrocytes become reactive and proliferative, disrupting the neurovascular unit in the lesioned area, especially in the aged brain. Therefore, restoring the balance between neurons and nonneuronal cells within the perilesional area is crucial for post stroke recovery. In addition, the aged post stroke brain mounts a fulminant proliferative astroglial response leading to the buildup of gliotic scars that prevent neural regeneration. Therefore, "melting" glial scars has been attempted for decades, albeit with little success. Alternative strategies include transforming inhibitory gliotic tissue into an environment conducive to neuronal regeneration and axonal growth by genetic conversion of astrocytes into neurons. The latter idea has gained momentum following the discovery that in vivo direct lineage reprogramming in the adult mammalian brain is a feasible strategy for reprogramming nonneuronal cells into neurons. This exciting new technology emerged as a new approach to circumvent cell transplantation for stroke therapy. However, the potential of this new methodology has not been yet tested to improve restoration of structure and function in the hostile environment caused by the fulminant inflammatory reaction in the brains of aged animals.

Memory and Learning Deficits Are Associated With Ca2+ Dyshomeostasis in Normal Aging

“…Despite the originality of our study, some limitations should be acknowledged. First, we explored intracellular Ca 2+ dysregulation as the only factor contributing to the pathogenesis of aging and not other hypotheses such as: (i) glial cell alterations (Popa-Wagner et al, 2019 ), (ii) blood-brain-barrier disruption (Fulop et al, 2019 ), (iii) alteration in circadian rhythms (Logan et al, 2018 ), and (iv) endothelial dysfunction (Tarantini et al, 2019 ). Second, we did not perform a dose-response curve on dantrolene and cognitive improvement.…”

New role of astrocytes in neuroprotective mechanisms after ischemic stroke

“…However, in response to cerebral ischemia, a growing number of studies have found that astrocytes in the striatum can be transformed into neurons. 32 33 Both in vivo and in vitro studies have shown that astrocytes have the characteristics of stem cells and can differentiate into neurons under certain conditions 34 35 36 37 ( Figure 2 ).…”

Oxidative Stress, Inflammation, and Autophagy: Potential Targets of Mesenchymal Stem Cells-Based Therapies in Ischemic Stroke

“…A1 astrocytes are derived from resting astrocytes stimulated by the inflammatory factors including TNF-α, IL-1α, and C1q generated from activated microglia (Liddelow et al, 2017), and A1 astrocyte has been ascertained to be elevated after cerebral ischemia. A1 activated astrocyte not only delivery inflammatory mediators, such as TNF-α, IL-1, glial fibrillary acidic protein (GFAP), and matrix metalloproteases (MMPs), but also promote the formation of glial scar and disrupt the BBB (Jayaraj et al, 2019;Popa-Wagner et al, 2019). Meanwhile, the infiltrated neutrophils, DCs, and lymphocytes also promote proinflammatory pathways via secreting inflammatory factors and endothelial adhesion molecules (Weston et al, 2007;Anrather and Iadecola, 2016).…”