Neonatal Med.  2019 Feb;26(1):1-16. 10.5385/nm.2019.26.1.1.

Human Neural Stem Cells: Translational Research for Neonatal Hypoxic-Ischemic Brain Injury

• Shin JE
• Han J
• Lim JH
• Eun HS
• Park KI

• KMID: 2440695
• DOI: http://doi.org/10.5385/nm.2019.26.1.1

Abstract

Neonatal hypoxic-ischemic (HI) brain injury is a major cause of neonatal mortality and long-term neurodevelopmental disabilities. Although promising neuroprotective interventions have been studied, the current management of HI brain injury has been limited to supportive measures and induced hypothermia. In addition to engrafting, migrating toward the damage sites and differentiating into multiple lineages, multipotent neural stem/progenitor cells (NSPCs) also provide trophic/immunomodulatory factors and integrate into the host neurons upon implantation into an HI-injured brain. However, NSPC-based therapies have shown poor cell survival and integration, poor differentiation or restricted differentiation into the glial lineages. Furthermore, to achieve full functional recovery following brain injury, the optimization of cell therapy is needed to recapitulate the precise migration of stem cells to the region of interest and the neural rewiring present in the brain microenvironment. Therefore, the efficacy of NSPCs in the treatment of CNS injury is currently insufficient. Human NSPCs (hNSPCs) were isolated from the forebrain of an aborted fetus at 13 weeks of gestation with full parental consent and the approval of the Institutional Review Board of the Yonsei University College of Medicine. Here, to enhance the regenerative ability of hNSPCs in HI brain injury, cells were either pretreated with pharmacological agents or engineered to serve as vehicles for gene delivery. Furthermore, when combined with a poly (glycolic acid)-based synthetic scaffold, hNSPCs provide a more versatile treatment for neonatal HI brain injury. Finally, hNSPCs transfected with zinc-doped ferrite magnetic nanoparticles for controlling both cell migration and differentiation offer a simple and smart tool for cell-based therapies.

Keyword

Neural stem cells; Hypoxia-ischemia, brain; Cell therapy; Genetic therapy

MeSH Terms

Aborted Fetus
Brain Injuries*
Brain*
Cell Movement
Cell Survival
Cell- and Tissue-Based Therapy
Ethics Committees, Research
Genetic Therapy
Humans*
Hypothermia, Induced
Hypoxia-Ischemia, Brain
Infant
Infant Mortality
Nanoparticles
Neural Stem Cells*
Neurons
Parental Consent
Pregnancy
Prosencephalon
Stem Cells
Translational Medical Research*

Figure

• 

  Figure 1. Transplantation (Tx) of human nucleus pulposus cell (hNPC)-poly (glycolic acid) (PGA) complexes into the infarction cavity of a hypoxic-ischemic (HI) brain injury. (A) Two weeks following Tx of the hNPC-PGA complexes (an arrow) into the infarction cavity indicated by an asterisk; human nuclei (hNuc)+donor-derived cells (green) show robust engraftment within the injured area. The PGA fibers begin to biodegrade (green strands, arrowheads). (B-G) Some human neural stem/progenitor cell (hNSPC)+donor-derived cells (red in B, D, E, G) presented co-localization with neurofilament (NF) (blue arrows in B, C, D) with either extended neuronal processes (white arrows in C, D; n=15) or glial fibrillary acidic protein (GFAP) (white arrows in E, F, G; n=15). The PGA fibers are indicated by arrowheads in B-G. The tract tracer biotinylated dextran amine conjugated with fluorescein (BDA-FITC) was injected into the contralateral intact cortex at 10 weeks following implantation of the hNPC-PGA complex into the infarction cavity. Axonal projections were labeled in green with fluorescein and can be visualized from the cerebral cortex as well as the external capsule (EC) of the intact hemisphere, projecting through the corpus callosum (CC) and toward the implantation site of the hNPC-PGA complex within the injured ipsilateral cortex and penumbra (H). Some BDA-FITC+anterograde-labeled processes from the neurons in the contralateral intact hemisphere were observed to sprout their axons toward the implantation site of the hNPC-PGA complex (H). The BDA-FITC+retrograde-labeled cell body and cellular processes of a neuron-like cell in the ipsilateral cortical penumbra indicated by an asterisk (in H) are well visualized at a higher magnification (I). The data shown are representative images. Scale bars (A, H: 500 μm; B, E: 20 μm).

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