Clinical-grade human umbilical cord-derived mesenchymal stem cells reverse cognitive aging via improving synaptic plasticity and endogenous neurogenesis

Abstract

Cognitive aging is a leading public health concern with the increasing aging population, but there is still lack of specific interventions directed against it. Recent studies have shown that cognitive function is intimately affected by systemic milieu in aging brain, and improvement of systemic environment in aging brain may be a promising approach for rejuvenating cognitive aging. Here, we sought to study the intervention effects of clinical-grade human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on cognitive aging in a murine model of aging. The conventional aging model in mice induced by d-galactose (d-gal) was employed here. Mice received once every two weeks intraperitoneal administration of hUC-MSCs. After 3 months of systematical regulation of hUC-MSCs, the hippocampal-dependent learning and memory ability was effectively improved in aged mice, and the synaptic plasticity was remarkably enhanced in CA1 area of the aged hippocampus; moreover, the neurobiological substrates that could impact on the function of hippocampal circuits were recovered in the aged hippocampus reflecting in: dendritic spine density enhanced, neural sheath and cytoskeleton restored, and postsynaptic density area increased. In addition, the activation of the endogenic neurogenesis which is beneficial to stabilize the neural network in hippocampus was observed after hUC-MSCs transplantation. Furthermore, we demonstrated that beneficial effects of systematical regulation of hUC-MSCs could be mediated by activation of mitogen-activated protein kinase (MAPK)-ERK-CREB signaling pathway in the aged hippocampus. Our study provides the first evidence that hUC-MSCs, which have the capacity of systematically regulating the aging brain, may be a potential intervention for cognitive aging.

HGF Mediates Clinical‐Grade Human Umbilical Cord‐Derived Mesenchymal Stem Cells Improved Functional Recovery in a Senescence‐Accelerated Mouse Model of Alzheimer's Disease

“…[ 28 ] Indeed, while the use of animal components carries the risk of zoonoses and xenogeneic immune reactions, [ 29 ] laboratory‐generated hUC‐MSCs do not undergo quality and safety testing that is required for clinical applications. Our group has established a Cell Factory and Biobank at the South China Institute of Biomedicine in Guangzhou that is currently producing clinical‐grade hUC‐MSCs, using methods [ 14 ] that are fully compliant with current Good Manufacturing Practice guidelines, and conform to the quality standards of National Institutes for Food and Drug Control.…”

“…Our past work has characterized beneficial effects of clinical‐grade hUC‐MSC‐based therapies for intervening with normal aging‐related cognitive dysfunction. [ 14 ] However, whether hUC‐MSCs have effects on pathological cognitive decline in AD, needs to be further addressed. Although some studies have showed positive effects of hUC‐MSCs in the treatment of AD, [ 30,31 ] little is known about which core factor secreted from hUC‐MSCs plays important roles in hUC‐MSC‐modulated recovery of cognition function, which may be one of the key factors restricting the better clinical application of hUC‐MSCs.…”

“…Recently, our group optimized transplantation parameters and established several benefits of hUC‐MSC‐based interventions for normal aging‐related cognitive decline. [ 14 ] We demonstrated that the intraperitoneal administration of clinical‐grade hUC‐MSCs could counteract cognitive aging of synaptic plasticity, neural networks, molecular regulation, and cognition in aged mice; these effects were systemic and integrated, suggesting that hUC‐MSCs may be a preferred resource to systematically regulate the aging brain and interpose the physiological processes of cognitive aging. [ 14 ] However, whether the hUC‐MSCs are a better choice for treating pathological cognitive decline in the aging brain, especially for AD, still needs to be further addressed.…”

“…[ 14 ] We demonstrated that the intraperitoneal administration of clinical‐grade hUC‐MSCs could counteract cognitive aging of synaptic plasticity, neural networks, molecular regulation, and cognition in aged mice; these effects were systemic and integrated, suggesting that hUC‐MSCs may be a preferred resource to systematically regulate the aging brain and interpose the physiological processes of cognitive aging. [ 14 ] However, whether the hUC‐MSCs are a better choice for treating pathological cognitive decline in the aging brain, especially for AD, still needs to be further addressed. Therefore, we hypothesized that hUC‐MSCs, as young stem cells, [ 15 ] may be a superior source for interposing or reversing AD.…”

ESC‐sEVs Rejuvenate Senescent Hippocampal NSCs by Activating Lysosomes to Improve Cognitive Dysfunction in Vascular Dementia

“…D‐galactose (D‐gal) induced aging model is a systemic and homogeneous aging model, [ 55 ] it was applied to induce NSCs senescence in vitro as described before. [ 56 ] Senescent NSCs were incubated with 1 × 10 10 particles per mL ESC‐sEVs or an equal volume of PBS for 3 passages.…”