Age-dependent regenerative mechanisms in the brain

Abstract

Repairing the adult mammalian brain represents one of the greatest clinical challenges in medicine. Injury to the adult brain often results in substantial loss of neural tissue and permanent functional impairment. In contrast with the adult, during development, the mammalian brain exhibits a remarkable capacity to replace lost cells. A plethora of cell-intrinsic and extrinsic factors regulate the age-dependent loss of regenerative potential in the brain. As the developmental window closes, neural stem cells undergo epigenetic changes, limiting their proliferation and differentiation capacities, whereas, changes in the brain microenvironment pose additional challenges opposing regeneration, including inflammation and gliosis. Therefore, studying the regenerative mechanisms during development and identifying what impairs them with age may provide key insights into how to stimulate regeneration in the brain. Here, we will discuss how the mammalian brain engages regenerative mechanisms upon injury or neuron loss. Moreover, we will describe the age-dependent changes that affect these processes. We will conclude by discussing potential therapeutic approaches to overcome the age-dependent regenerative decline and stimulate regeneration.

Keywords: adaptive reprogramming; neural stem cells; regeneration; rodent brain.

Figure 1.. Potential regenerative mechanisms and age-dependent changes in the brain.

(A) Hypothetical schematic of neural stem cell (NSC) lineages during development and homeostasis (oligodendrocytes were omitted). (B) Potential mechanisms of neuron regeneration mediated by (i) compensatory proliferation of NSCs or transit amplifying cells [18–20] (blue), (ii) immature neuron progenitors or neurons re-entering the cell cycle [29] (green), (iii) adaptive reprogramming of NSCs, gliogenic progenitors or astroglia [28,32–35] (red), (iv) astrocytes acquiring stemness or neurogenic potential upon injury [25,26] (yellow). (C) Cell-intrinsic and -extrinsic changes that occur during development and ageing in the brain.