Transplanted OE-MSCs were found to migrate to sites of damage, differentiate into neurons, and restore memory and learning.
Studies have shown that a recently identified type of human stem cell located in the nasal cavity can help repair brain damage and restore associated learning and memory when transplanted into experimental mice. Researchers have found that human olfactory ectomesenchymal stem cells (OE-MSCs) transplanted either directly into the brain tissue or into the cerebrospinal fluid of nonimmunosuppressed mice, migrated to sites of neural damage, differentiated into neurons, and stimulated endogenous neurogenesis.
The work was conducted by Emmanuel Nivet, Ph.D., at the laboratories of France’s Centre National de la Recherche Scientifique, and colleagues. The team reports its findings in The Journal of Clinical Investigation. Their paper is titled “Engraftment of human nasal olfactory stem cells restores neuroplasticity in mice with hippocampal lesions.”
OE-MSCs are located in the lamina propria of the human olfactory mucosa within the nasal cavity, which is an easily accessible tissue that can be harvested under local anesthesia, the French team explains. Transcript and membrane protein analyses have in addition previously shown that OE-MSCs are closely related to bone marrow mesenchymal stem cells (BM-MSCs) but in comparison with BM-MSCs exhibit a high-level expression of genes involved in neurogenesis.
To evaluate the neurogenic potential of human OE-MSCs in vivo, the researchers carried out a series of transplantation experiments in a mouse model of excitotoxically induced cell death that mimics the effects of an ischemic/hypoxic injury in the hippocampus. They first confirmed that the mouse hippocampus represented a suitable environment for neural differentiation of the human cells in vitro by applying GFP-expressing OE-MSCs to mouse hippocampal slices.
Three weeks after grafting a proportion of the surviving GFP-positive transplanted cells displayed an interneuron-like morphology and/or expressed MAP2 mature neuronal markers. Some also exhibited electrophysioloigical properties consistent with immature neurons.
The team then generated a nonimmunosuppressed mouse model with hippocampal damage and associated memory dysfunction induced by ibotenic acid. Compared with normal mice, these animals were unable to learn a cue-reward association to which normal mice had rapidly learned to respond. Human GFP+ OE-MSS were then grafted into the hippocampus of a cohort of the lesioned mice. Four weeks later these experimental animals displayed significant improvements in the ability to perform correct associations in comparison with control, sham-grafted animals. After five training sessions the OE-MSC recipients exhibited scores close to those of normal control mice.
In a second cohort of similarly brain-damaged mice, OE-MSC transplantation into the hippocampus improved lesion-related deficits in visuospatial learning and reference memory. Subsequent tests on brain tissue isolated from the animals showed that by five weeks after transplantation, the human OE-MSCs had settled within the hippocampus.
Up to 80% of these cells expressed the immature neuron marker III-β-tubulin and up to 1.3% were positive for MAP2, a marker of mature neurons. None were positive for glial cell markers. The transplanted neurons were also found in other cerebral areas but in none of the peripheral structures tested, including kidney, liver, or lung. Interestingly, and in contrast with data from other research, the scientists note, none of the OE-MSCs differentiated into astrocytes, either in the in vitro co-culture tests or in the subsequent in vivo experiments.
In a further set of in vivo tests the researchers used the same brain-damaged mouse model but grafted the GFP-positive human OE-MSCs into the cerebrospinal fluid of lateral ventricles rather than directly into the hippocampus. Behavioral evaluation after four weeks confirmed that the treated animals demonstrated improved capacity compared with sham-grafted animals.
Improved performances in the OE-MSC-recipients were associated with the presence of GFP+ cells in different layers of the hippocampus and evident neurogenesis; stem cells had differentiated into cells expressing neuron-specific markers. Again, no GFP+ cells were found in any peripheral structures, but neural marker-negative GFP+ cells were found at the margin of ventricular areas.
The team suggests the results of their studies support the potential use of OE-MSCs for repairing damaged or diseased brains. Encouragingly, even though the murine model they used for experimentation received no immunosuppressant, nearly 20% of the human OE-MSCs that were transplanted migrated into hippocampal neuronal layers and nearly 70% of these differentiated into cells expressing neuronal markers.
In addition, Dr. Nivet and colleagues say data not presented in the published studies showed that OE-MSCs express several chemokine receptors and are responsive to overexpressed molecules that stimulate their migration. “It is therefore not surprising that OE-MSCs can home to lesioned sites and this selective migration is a critical step in stem cell regeneration therapies,” they point out.
“Although previous studies have demonstrated hippocampal plasticity after cell transplantation, to the best of our knowledge, no study using human adult stem cells has ever demonstrated that cell therapy can induce the restoration of functional neuronal networks within the adult hippocampus,” the researchers conclude.
“Indeed, among all the cell types proposed for the future regenerative medicine of the CNS, OE-MSCs have the enormous advantage of being easily accessible in living adults, obtainable under local anesthesia, and transplantable in an autologous manner, thus eliminating contentious ethical and technical considerations.”