Stem Cell Therapy for Neuroprotection in the Growth-Restricted Newborn

Abstract

Fetal growth restriction (FGR) occurs when a fetus is unable to grow normally due to inadequate nutrient and oxygen supply from the placenta. Children born with FGR are at high risk of lifelong adverse neurodevelopmental outcomes, such as cerebral palsy, behavioral issues, and learning and attention difficulties. Unfortunately, there is no treatment to protect the FGR newborn from these adverse neurological outcomes. Chronic inflammation and vascular disruption are prevalent in the brains of FGR neonates and therefore targeted treatments may be key to neuroprotection. Tissue repair and regeneration via stem cell therapies have emerged as a potential clinical intervention for FGR babies at risk for neurological impairment and long-term disability. This review discusses the advancement of research into stem cell therapy for treating neurological diseases and how this may be extended for use in the FGR newborn. Leading preclinical studies using stem cell therapies in FGR animal models will be highlighted and the near-term steps that need to be taken for the development of future clinical trials.

Keywords: endothelial progenitor cells; fetal growth retardation; mesenchymal stromal cells; newborn brain; stem cells.

Fetal growth restriction (FGR) results in significant neurodevelopmental issues via chronic ischemia that can lead to lifelong physical and mental disabilities. This review highlights the latest research in the development of stem cell therapies in preclinical and clinical trials aiming at repairing and reversing the neuronal damage, as well as discussing the gaps that remain in this field of research.

Figure 1.

Potential structural and cellular changes associated with the neuropathology of fetal growth restriction (FGR) newborn. Chronic exposure to reduced oxygen and nutrient supply elicits an ongoing pro-inflammatory environment for the developing brain. Microglia and astrocytes display the maladaptive inflammatory response, with activated/reactive morphology and the release of pro-inflammatory cytokines, such as interleukin-1β, TNF, and CXCL10, further exacerbating the inflammatory response. Altered interaction of astrocytes with microvessels may be associated with the influx of peripheral infiltrates, such as serum proteins (IgG) and T cells (CD³⁺). There is also evidence of altered vasculature which may worsen oxygen and nutrient supply to cellular bodies during postnatal development hindering maturation and repair. Impaired myelination of white matter regions is associated with decreased oligodendrocyte expression. FGR newborn brains displayed reduced numbers of mature neuronal cells throughout the somatosensory cortex. Altered neuronal populations and connectivity, due to disrupted white matter tracts, may be associated with deficits with the integration of information from different modalities. Illustration created with Biorender.com.