Human Umbilical Cord Mesenchymal Stem Cells Preserve Adult Newborn Neurons and Reduce Neurological Injury after Cerebral Ischemia by Reducing the Number of Hypertrophic Microglia/Macrophages

Abstract

Microglia are the first source of a neuroinflammatory cascade, which seems to be involved in every phase of stroke-related neuronal damage. Two weeks after transient middle cerebral artery occlusion (MCAO), vehicle-treated rats displayed higher numbers of total ionized calcium-binding adaptor molecule 1 (Iba-1)-positive cells, greater cell body areas of Iba-1-positive cells, and higher numbers of hypertrophic Iba-1-positive cells (with a cell body area over 80 μm2) in the ipsilateral ischemic brain regions including the frontal cortex, striatum, and parietal cortex. In addition, MCAO decreased the number of migrating neuroblasts (or DCX- and 5-ethynyl-2′-deoxyuridine-positive cells) in the cortex, subventricular zone, and hippocampus of the ischemic brain, followed by neurological injury (including brain infarct and neurological deficits). Intravenous administration of human umbilical cord–derived mesenchymal stem cells (hUC-MSCs; 1 × 106 or 4 × 106) at 24 h after MCAO reduced neurological injury, decreased the number of hypertrophic microglia/macrophages, and increased the number of newborn neurons in rat brains. Thus, the accumulation of hypertrophic microglia/macrophages seems to be detrimental to neurogenesis after stroke. Treatment with hUC-MSCs preserved adult newborn neurons and reduced functional impairment after transient cerebral ischemia by reducing the number of hypertrophic microglia/macrophages.

Umbilical cord-derived mesenchymal stromal cells immunomodulate and restore actin dynamics and phagocytosis of LPS-activated microglia via PI3K/Akt/Rho GTPase pathway

“…Recently, Rho GTPases, Rac1 and Cdc42, have been shown to regulate Fc receptor-mediated phagocytosis by controlling the different steps of membrane and actin dynamics, leading to particle engulfment (25,30). Similar to that shown previously (31), MSCs signi cantly changed the morphology of LPS-activated microglia in our study. Our results revealed that the number of branches, junctions, and processes decreased after LPS stimulation and signi cantly increased after MSC co-culture.…”

Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells on the Acute Cigarette Smoke-Induced Pulmonary Inflammation Model

“…Compared with bone marrow-and gingival tissue-derived MSCs, hUC-MSCs have been determined to display the highest immunomodulatory ability (Li et al, 2018). Doses of hUC-MSC between 1 × 10 6 and 4 × 10 6 cells/ml have been deemed effective in a previous study (Chen et al, 2005;Carter and Misra, 2010;Lin et al, 2017). For example, the hUC-MSC concentration of 3 × 10 6 cells/ml was administered in lung disease (Zhang et al, 2018).…”

Optimizing Stem Cell Therapy after Ischemic Brain Injury

“…77 Additionally, IV injection of UC-BSCs (1×10 6 or 4×10 6 ), 1 day after ischemic injury, has been shown to reduce neurological injury in stroke rats. 118 Regarding timing, MSCs administered 3 or 10 days postneonatal hypoxic ischemic injury showed significant improvements in motor behavior, while administration at 17 days showed neither sensorimotor function improvement nor gray/ white matter loss reduction. This suggests a broader treatment window for intranasal MSC delivery, particularly when compared to the current treatment window of 6 hours for therapeutic hypothermia, which is the current standard of care.…”