An implantable human stem cell-derived tissue-engineered rostral migratory stream for directed neuronal replacement

The rostral migratory stream (RMS) facilitates neuroblast migration from the subventricular zone to the olfactory bulb throughout adulthood. Brain lesions attract neuroblast migration out of the RMS, but resultant regeneration is insufficient. Increasing neuroblast migration into lesions has improved recovery in rodent studies. We previously developed techniques for fabricating an astrocyte-based Tissue-Engineered RMS (TE-RMS) intended to redirect endogenous neuroblasts into distal brain lesions for sustained neuronal replacement. Here, we demonstrate that astrocyte-like-cells can be derived from adult human gingiva mesenchymal stem cells and used for TE-RMS fabrication. We report that key proteins enriched in the RMS are enriched in TE-RMSs. Furthermore, the human TE-RMS facilitates directed migration of immature neurons in vitro. Finally, human TE-RMSs implanted in athymic rat brains redirect migration of neuroblasts out of the endogenous RMS. By emulating the brain’s most efficient means for directing neuroblast migration, the TE-RMS offers a promising new approach to neuroregenerative medicine.

Neuronal Replacement in Stem Cell Therapy for Stroke: Filling the Gap

Stem cell therapy using human skin-derived neural precursors holds much promise for the treatment of stroke patients. Two main mechanisms have been proposed to give rise to the improved recovery in animal models of stroke after transplantation of these cells. First, the so called by-stander effect, which could modulate the environment during early phases after brain tissue damage, resulting in moderate improvements in the outcome of the insult. Second, the neuronal replacement and functional integration of grafted cells into the impaired brain circuitry, which will result in optimum long-term structural and functional repair. Recently developed sophisticated research tools like optogenetic control of neuronal activity and rabies virus monosynaptic tracing, among others, have made it possible to provide solid evidence about the functional integration of grafted cells and its contribution to improved recovery in animal models of brain damage. Moreover, previous clinical trials in patients with Parkinson’s Disease represent a proof of principle that stem cell-based neuronal replacement could work in humans. Our studies with in vivo and ex vivo transplantation of human skin-derived cells neurons in animal model of stroke and organotypic cultures of adult human cortex, respectively, also support the hypothesis that human somatic cells reprogrammed into neurons can get integrated in the human lesioned neuronal circuitry. In the present short review, we summarized our data and recent studies from other groups supporting the above hypothesis and opening new avenues for development of the future clinical applications.

Allogeneic Neural Stem Cell Transplant Promotes Functional Recovery of Locomotion After Complete Transected Spinal Cord Injury Predominantly by Secreting Neurotrophic Factors

ObjectiveCell-based therapy is a promising strategy for spinal cord injury (SCI) repair, but faced the challenges to direct the neuronal differentiation of appropriate neuron subtypes for achieving the neuronal replacement. We investigated whether allogeneic beforehand in vitro differentiated neural stem cells (NSCs) could relieve the adverse effects of regeneration inhibitory niche and promote motor functional recovery by accomplishing neuronal replacement after transplant into SCI rats. MethodsCollagen scaffold combined with digested NSCs, NSC sphere, differentiated neurons, and sphere of differentiated neurons were transplanted into completely transected SCI in rats and therapeutic outcomes were investigated. Next, we enriched complex of neurotrophic factors secreted from culture medium of NSCs, neurons, and sphere of neurons and a total of 2 mg total enriched protein combined with collagen scaffold were transplanted into SCI to further assay whether allogeneic NSCs transplant promotes the recovery of SCI predominantly by secreting neurotrophic factors. ResultsNSCs differentiated into neurons in density-dependent manner in vitro and sphere of NSCs could counteract myelin-induced inhibition of neuronal differentiation. Collagen scaffold combined with digested NSCs, NSC sphere, differentiated neurons, and sphere of differentiated neurons were transplanted into completely transected SCI in rats. Overall the cell treatment groups had a much better locomotor recovery, tissue remodeling, and newborn neuron formation than alone collagen scaffold treatment, compared with alone collagen material transplant and control group. However, unexpectedly, the differentiated cell treatment (differentiated neurons and sphere of differentiated neurons transplants) did not present striking better locomotor recovery than the undifferentiated NSCs and sphere of NSCs treatments, only sphere of neurons showed a slight increase in BBB score compared to other cell treatments. Next, we enriched complex of neurotrophic factors secreted from culture medium of NSCs, neurons, and sphere of neurons. BBB score analysis showed that the secreted neurotrophic factors from NSCs, neurons, and sphere of neurons would promote functional recovery of SCI to the same extent. ConclusionAllogeneic NSCs transplant promotes functional recovery of SCI predominantly by secreting neurotrophic factors, not direct neuronal replacement of differentiated neurons from transplanted cells.