Human Adult Dental Pulp Stem Cells Enhance Poststroke Functional Recovery Through Non-Neural Replacement Mechanisms

Abstract

Human adult dental pulp stem cells (DPSCs), derived from third molar teeth, are multipotent and have the capacity to differentiate into neurons under inductive conditions both in vitro and following transplantation into the avian embryo. In this study, we demonstrate that the intracerebral transplantation of human DPSCs 24 hours following focal cerebral ischemia in a rodent model resulted in significant improvement in forelimb sensorimotor function at 4 weeks post-treatment. At this time, 2.3 ± 0.7% of engrafted cells had survived in the poststroke brain and demonstrated targeted migration toward the stroke lesion. In the peri-infarct striatum, transplanted DPSCs differentiated into astrocytes in preference to neurons. Our data suggest that the dominant mechanism of action underlying DPSC treatment that resulted in enhanced functional recovery is unlikely to be due to neural replacement. Functional improvement is more likely to be mediated through DPSC-dependent paracrine effects. This study provides preclinical evidence for the future use of human DPSCs in cell therapy to improve outcome in stroke patients.

Effect of Extracellular Vesicles on Neural Functional Recovery and Immunologic Suppression after Rat Cerebral Apoplexy

“…Many categories of cerebral apoplexy models have shown that nerve protection was primarily terminated through an indirect mechanism. Recent studies have reported that stem cell-derived extracellular vesicles exert an effect on alleviating movement coordination disorders after focal cerebral ischemia [10,11]. In the current study, we compared and found that extracellular vesicles and MSCs possess an identical effect.…”

Dental Pulp Stem Cell Niche

“…NGF and its receptor tropomyosin-related kinase A (TrkA) play a crucial role in the development and function of the nervous system. DPSCs exert an intriguing regenerative potential in the damaged central nervous system of the rodent, that is attributed in part to their multiple-differentiation ability to replace lost neurons, but mainly to the production of neurotrophic factors including NGF and brain derived neurotrophic factor (BDNF) that promote neuron survival and axon guidance [92,93]. NGF is involved in the guidance of trigeminal axons in embryonic teeth.…”

Adult human dental pulp stem cells promote blood–brain barrier permeability through vascular endothelial growth factor-a expression

“…However, this is a highly invasive procedure and is associated with an increased mortality rate of approximately 10% when administered acutely in rodent stroke models. 2 As such, acute IC transplantation may not be a clinically viable model.…”

“…2 This field of study was sparked by the ability of stem cells to populate areas and replace the function of many divergent tissue types. Transplantation of stem cells provides the potential to extend the post-stroke recovery of function beyond what is possible by endogenous recovery alone.…”

“…[13][14][15] Intracerebral (IC) transplantation following stroke in a rat model showed an improvement in functional outcomes. 2 There are two paradigms for the administration of therapeutic stem cells in stroke research: intravascular (IV) and IC. IC transplantation delivers stem cells directly to the site of damage, which may result in a greater surviving population of viable cells.…”