The endogenous regenerative capacity of the damaged newborn brain: boosting neurogenesis with mesenchymal stem cell treatment

Abstract

Neurogenesis continues throughout adulthood. The neurogenic capacity of the brain increases after injury by, e.g., hypoxia-ischemia. However, it is well known that in many cases brain damage does not resolve spontaneously, indicating that the endogenous regenerative capacity of the brain is insufficient. Neonatal encephalopathy leads to high mortality rates and long-term neurologic deficits in babies worldwide. Therefore, there is an urgent need to develop more efficient therapeutic strategies. The latest findings indicate that stem cells represent a novel therapeutic possibility to improve outcome in models of neonatal encephalopathy. Transplanted stem cells secrete factors that stimulate and maintain neurogenesis, thereby increasing cell proliferation, neuronal differentiation, and functional integration. Understanding the molecular and cellular mechanisms underlying neurogenesis after an insult is crucial for developing tools to enhance the neurogenic capacity of the brain. The aim of this review is to discuss the endogenous capacity of the neonatal brain to regenerate after a cerebral ischemic insult. We present an overview of the molecular and cellular mechanisms underlying endogenous regenerative processes during development as well as after a cerebral ischemic insult. Furthermore, we will consider the potential to use stem cell transplantation as a means to boost endogenous neurogenesis and restore brain function.

Figures

Figure 1

Neurogenesis and migration in the subventricular zone (SVZ) and subgranular zone (SGZ) after hypoxia–ischemia (HI) and mesenchymal stem cell (MSC) treatment. Schematic overview of the neurogenic niche in the SVZ and SGZ. Neural progenitors in the SVZ differentiate into neuroblasts (Dcx+), which not only migrate toward the damaged striatum, but also through radial migration along the corpus callosum toward cortical regions. Neuroblasts in the SGZ migrate along radial astrocytes toward the granular cell layer GCL in the dentate gyrus (DG). HI insult induces the production of several factors that promote neurogenesis and migration in the damaged areas. MSC administration increases the production of several factors that are involved in cell proliferation, differentiation, and migration. Cb, cerebellum; CC, corpus callosum; Cx, cortex; Dcx, doublecortin; EGFR, epidermal growth factor receptor; gcl, granular cell layer; GDNF, glial cell-derived neurotrophic factor; gp130, glycoprotein 130; LV, lateral ventricle; MMP, matrix metalloproteinase; OB, olfactory bulb; sgz, subgranular zone; VEGF, vascular endothelial growth factor.