Delayed Double Treatment with Adult-Sourced Adipose-Derived Mesenchymal Stem Cells Increases Striatal Medium-Spiny Neuronal Number, Decreases Striatal Microglial Number, and Has No Subventricular Proliferative Effect, after Acute Neonatal Hypoxia-Ischemia in Male Rats

Abstract

Perinatal hypoxia-ischemia (HI) is a major cause of striatal injury. Delayed post-treatment with adult-sourced bone marrow-derived mesenchymal stem cells (BMSCs) increased the absolute number of striatal medium-spiny neurons (MSNs) following perinatal HI-induced brain injury. Yet extraction of BMSCs is more invasive and difficult compared to extraction of adipose-derived mesenchymal stem cells (AD-MSCs), which are easily sourced from subcutaneous tissue. Adult-sourced AD-MSCs are also superior to BMSCs in the treatment of adult ischemic stroke. Therefore, we investigated whether delayed post-treatment with adult-sourced AD-MSCs increased the absolute number of striatal MSNs following perinatal HI-induced brain injury. This included investigation of the location of injected AD-MSCs within the brain, which were widespread in the dorsolateral subventricular zone (dlSVZ) at 1 day after their injection. Cells extracted from adult rat tissue were verified to be stem cells by their adherence to tissue culture plastic and their expression of specific ‘cluster of differentiation’ (CD) markers. They were verified to be AD-MSCs by their ability to differentiate into adipocytes and osteocytes in vitro. Postnatal day (PN) 7/8, male Sprague-Dawley rats were exposed to either HI right-sided brain injury or no HI injury. The HI rats were either untreated (HI + Diluent), single stem cell-treated (HI + MSCs×1), or double stem cell-treated (HI + MSCs×2). Control rats that were matched-for-weight and litter had no HI injury and were treated with diluent (Uninjured + Diluent). Treatment with AD-MSCs or diluent occurred either 7 days, or 7 and 9 days, after HI. There was a significant increase in the absolute number of striatal dopamine and cyclic AMP-regulated phosphoprotein (DARPP-32)-positive MSNs in the double stem cell-treated (HI + MSCs×2) group and the normal control group compared to the HI + Diluent group at PN21. We therefore investigated two potential mechanisms for this effect of double-treatment with AD-MSCs. Specifically, did AD-MSCs: (i) increase the proliferation of cells within the dlSVZ, and (ii) decrease the microglial response in the dlSVZ and striatum? It was found that a primary repair mechanism triggered by double treatment with AD-MSCs involved significantly decreased striatal inflammation. The results may lead to the development of clinically effective and less invasive stem cell therapies for neonatal HI brain injury.

Perinatal Tissue-Derived Stem Cells: An Emerging Therapeutic Strategy for Challenging Neurodegenerative Diseases

“…Several pieces of experimental evidence support the idea that the transplantation of MSCs is associated with an improvement in synaptic plasticity [49][50][51][52][53][54][55]. MSCs have also been reported to ameliorate cognitive performance in different animal models of NDDs, including AD [56][57][58][59][60][61][62], thus suggesting that this can represent a promising therapeutic strategy.…”

A Novel Rat Model of ADHD-like Hyperactivity/Impulsivity after Delayed Reward Has Selective Loss of Dopaminergic Neurons in the Right Ventral Tegmental Area

“…Some of the stereological methods used were not computerized, yet they are still valid practical approaches [52]. It is acknowledged that computerized approaches are more common now (e.g., [84]).…”

Progress in Research on Stem Cells in Neonatal Refractory Diseases

“…Hypothermia does not significantly reduce brain damage primarily by reducing energy depletion and increasing intracellular calcium ion levels [ 72 ]. In a study of HIE in term newborns and stroke in adults, MSCs played a major role in boosting the proliferation and differentiation of nerve cells and regulating or suppressing the local immune response of microglia and T lymphocytes [ 73 ]. In addition, MSCs and exosomes secreted by hPSCs may be a promising treatment for neuronal injury by interacting with parenchymal cells in the brain, resulting in reduced expression of axonal inhibitors and increased production of neuroprotective factors, thereby affecting axonal growth and promoting the restoration of normal nerve function [ 74 ].…”

“…Studies have shown that delayed administration (1 week after HIE) of large doses of BM-MSCs (7.5 × 10 5 –1.0 × 10 6 cells) can restore neurons projected from the striatum and improve motor function [ 80 ]. Other studies have suggested that delaying the administration of double high doses of hADSCs (PN14, PN16, ih, 1.07 × 10 6 , qd) in HIE rats significantly increases the absolute number of dorsal striatum dopamine and cyclic adenylate-regulated phosphoprotein-positive spinel neurons to normal undamaged levels [ 73 ]. Donega et al found that MSCs could be found at the site of injury 10 days after HIE, but not at 17 days, proving that the SC treatment window is at least 10 days, significantly extending the time window for hypothermia and bringing more hope for children with HIE [ 81 ].…”