Age of donor of human mesenchymal stem cells affects structural and functional recovery after cell therapy following ischaemic stroke

Abstract

Cell transplantation therapy offers great potential to improve impairments after stroke. However, the importance of donor age on therapeutic efficacy is unclear. We investigated the regenerative capacity of transplanted cells focusing on donor age (young vs. old) for ischaemic stroke. The quantities of human mesenchymal stem cell (hMSC) secreted brain-derived neurotrophic factor in vitro and of monocyte chemotactic protein-1 at day 7 in vivo were both significantly higher for young hMSC compared with old hMSC. Male Sprague-Dawley rats subjected to transient middle cerebral artery occlusion that received young hMSC (trans-arterially at 24 h after stroke) showed better behavioural recovery with prevention of brain atrophy compared with rats that received old hMSC. Histological analysis of the peri-infarct cortex showed that rats treated with young hMSC had significantly fewer microglia and more vessels covered with pericytes. Interestingly, migration of neural stem/progenitor cells expressing Musashi-1 positively correlated with astrocyte process alignment, which was more pronounced for young hMSC. Aging of hMSC may be a critical factor that affects cell therapy outcomes, and transplantation of young hMSC appears to provide better functional recovery through anti-inflammatory effects, vessel maturation, and neurogenesis potentially by the dominance of trophic factor secretion.

Obesity is associated with senescence of mesenchymal stromal cells derived from bone marrow, subcutaneous and visceral fat of young mice

“…Furthermore, many in vivo parameters (sex, age, co-morbidities) may impair a meaningful readout of senescence process. We then selected only young male animals to reduce variability, since chronological aging and estrogen fluctuation may influence MSC functions [ 24 – 26 ]. Further studies should be performed to evaluate the effects of age and sex on MSC dysfunction associated with obesity.…”

Senescent mesenchymal stem/stromal cells and restoring their cellular functions

“…Also, in the peri-infarct cortex of rats subjected to transient middle cerebral artery occlusion, aged MSC administration resulted in more microglia and reduced pericyte infiltration compared with that for young MSCs. The changes in cellular components probably correlated with reduced expression of brain-derived neurotrophic factor and MCP-1[ 96 ]. In a myocardial infarction (MI) model, the infusion of old MSCs resulted in a switch of the cellular profile in the infarct region.…”

Stem cell therapy for neurological disorders: A focus on aging

“…Young human mesenchymal stem cells (hMSCs) produce fewer microglia following transplantation in ischemic stroke, demonstrating that inflammation and immune response are more likely to produce efficient clean-up of tumor necrosis factors (TNFs) post-stroke. Histological analysis of aged hMSC transplantation revealed increased numbers of microglia and pericyte covered vessels, further supporting the lack of efficient control of inflammation (Yamaguchi et al, 2017). Aging has a mechanism of action that involves decreased Notch signaling which then causes downregulation of satellite cell regeneration.…”