Human Neural Stem Cell Grafts Modify Microglial Response and Enhance Axonal Sprouting in Neonatal Hypoxic–Ischemic Brain Injury

Abstract

Background and Purpose Hypoxic-Ischemic (HI) brain injury in newborn infants represents a major cause of cerebral palsy, development delay and epilepsy. Stem cell-based therapy has the potential to rescue and replace the ischemic tissue caused by HI and to restore function. However, the mechanisms by which stem cell transplants induce functional recovery are yet to be elucidated. In the present study, we sought to investigate the efficacy of human neural stem cells (hNSCs) derived from human embryonic stem cells (hESCs), in the rat model of neonatal HI and the mechanisms enhancing brain repair. Methods The hNSCs were genetically engineered for in vivo molecular imaging and for postmortem histological tracking. Twenty-four hours after the induction of HI, animals were grafted with hNSCs into the forebrain. Motor behavioral tests were performed the fourth week after transplantation. We used immunocytochemistry and neuroanatomical tracing to analyze neural differentiation, axonal sprouting and microglia response. Treatment-induced changes in gene expression were investigated by microarray and quantitative PCR. Results Bioluminescence imaging (BLI) permitted longitudinal tracking of grafted hNSCs in real time. HI transplanted animals significantly improved in their use of the contralateral impeded forelimb and in the rotarod test. The grafts showed good survival, dispersion and differentiation. We observed an increase of uniformly distributed microglia cells in the grafted side. Anterograde neuronanatomical tracing demonstrated significant contralesional sprouting. Microarray analysis revealed upregulation of genes involved in neurogenesis, gliogenesis and neurotrophic support. Conclusions These results suggest that hNSC transplants enhance endogenous brain repair through multiple modalities in response to HI.

The Endogenous Regenerative Capacity of the Damaged Newborn Brain: Boosting Neurogenesis with Mesenchymal Stem Cell Treatment

“…Some key functions associated with an increased gene expression are cell growth, cell proliferation, nervous system development, and cell migration. Our findings are further supported by studies in which human NSCs were transplanted intracranially at 24 hours after HI inducing an increase in the expression of genes involved in neurogenesis (e.g., doublecortin), migration (e.g., CXCR4), and survival (e.g., glialderived neurotrophic factor) 34 (see Figure 1). Furthermore, studies show that MSCs 130 and human NSCs improve axonal sprouting and neurite plasticity by increasing the expression of factors like VEGF and Slit.…”

“…Recent work by our group and others support the concept that stem cell transplantation may have therapeutic potential with a relatively long time window by repairing the already damaged brain. [34][35][36][37][38][39] In this review, we will first give an overview of developmental events taking place in the normal postnatal mammalian brain with emphasis on neuronal migration, spine/axon pruning, synapse formation, and myelin formation. Subsequently, we will discuss recent findings showing the endogenous capacity of the neonatal brain to regenerate after HI insult and the molecular mechanisms underlying endogenous regenerative processes after brain damage.…”

Mesenchymal stem cells as a treatment for neonatal ischemic brain damage

“…After an extensive unilateral lesion in the brain, the contralesional hemisphere can contribute to partial recovery of motor function by remodeling of the corticospinal tract (73,74). However, within the damaged hemisphere, axonal remodeling also takes place (75).…”

Human-Induced Pluripotent Stem Cells form Functional Neurons and Improve Recovery After Grafting in Stroke-Damaged Brain

“…Human fetal NSCs also gave rise to mature neurons after transplantation into the stroke-damaged rat brain [7][8][9]. Transplanted NSCs may promote recovery without differentiating to neurons through several other mechanisms, for example, modulation of inflammation [10][11][12], neuroprotection [12], stimulation of angiogenesis [11,13,14], and enhancing brain plasticity [15][16][17].…”