A persistent barrier to the cure and treatment of neurological diseases is the limited ability of the central and peripheral nervous systems to undergo neuroregeneration and repair. Recent efforts have turned to regeneration of various cell types through cellular reprogramming of native cells as a promising therapy to replenish lost or diminished cell populations in various neurological diseases. This review provides an in-depth analysis of the current viral vectors, genes of interest, and target cellular populations that have been studied, as well as the challenges and future directions of these novel therapies. Furthermore, the mechanisms by which cellular reprogramming could be optimized as treatment in neurological diseases and a review of the most recent cellular reprogramming in vitro and in vivo studies will also be discussed.

Microglia are associated with a wide range of both neuroprotective and neuroinflammatory functions in the central nervous system (CNS) during development and throughout lifespan. Chronically activated and dysfunctional microglia are found in many diseases and disorders, such as Alzheimer’s disease, Parkinson’s disease, and CNS-related injuries, and can accelerate or worsen the condition. Transplantation studies designed to replace and supplement dysfunctional microglia with healthy microglia offer a promising strategy for addressing microglia-mediated neuroinflammation and pathologies. This review will cover microglial involvement in neurological diseases and disorders and CNS-related injuries, current microglial transplantation strategies, and different approaches and considerations for generating exogenic microglia.

Alzheimer’s disease (AD) is a devastating neurodegenerative disease with limited therapeutic options. Cellular transplantation of healthy exogenic neurons to replace and restore neuronal cell function has previously been explored in AD animal models, yet most of these transplantation methods have utilized primary cell cultures or donor grafts. Blastocyst complementation offers a novel approach to generate a renewable exogenic source of neurons. These exogenic neurons derived from stem cells would develop with the in vivo context of the inductive cues within a host, thus recapitulating the neuron-specific characteristics and physiology. AD affects many different cell types including hippocampal neurons and limbic projection neurons, cholinergic nucleus basis and medial septal neurons, noradrenergic locus coeruleus neurons, serotonergic raphe neurons, and limbic and cortical interneurons. Blastocyst complementation can be adapted to generate these specific neuronal cells afflicted by AD pathology, by ablating important cell type and brain region–specific developmental genes. This review discusses the current state of neuronal transplantation to replace specific neural cell types affected by AD, and the developmental biology to identify candidate genes for knockout in embryos for creating niches to generate exogenic neurons via blastocyst complementation.

Currently, there is a significant shortage of transplantable organs for patients in need. Interspecies chimerism and blastocyst complementation are alternatives for generating transplantable human organs in host animals such as pigs to meet this shortage. While successful interspecies chimerism and organ generation have been observed between evolutionarily close species such as rat and mouse, barriers still exist for more distant species pairs such as human–mouse, marmoset–mouse, human–pig, and others. One of the proposed barriers to chimerism is the difference in developmental stages between the donor cells and the host embryo at the time the cells are introduced into the host embryo. Hence, there is a logical effort to stage-match the donor cells with the host embryos for enhancing interspecies chimerism. In this study, we used an in silico approach to simultaneously stage-match the early developing embryos of four species, including human, marmoset, mouse, and pig based on transcriptome similarities. We used an unsupervised clustering algorithm to simultaneously stage-match all four species as well as Spearman’s correlation analyses to stage-match pairs of donor–host species. From our stage-matching analyses, we found that the four stages that best matched with each other are the human blastocyst (E6/E7), the gastrulating mouse embryo (E6–E6.75), the marmoset late inner cell mass, and the pig late blastocyst. We further demonstrated that human pluripotent stem cells best matched with the mouse post-implantation stages. We also performed ontology analysis of the genes upregulated and commonly expressed between donor–host species pairs at their best matched stages. The stage-matching results predicted by this study will inform in vivo and in vitro interspecies chimerism and blastocyst complementation studies and can be used to match donor cells with host embryos between multiple species pairs to enhance chimerism for organogenesis.

A growing need for organs and novel cell-based therapies has provided a niche for approaches like interspecies chimeras. To generate organs from one donor species in another host species requires techniques such as blastocyst complementation and gene editing to successfully create an embryo that has cells from both the donor and the host. However, the task of developing highly efficacious and competent interspecies chimeras is met by many challenges. These interspecies chimeric barriers impede the formation of chimeras, often leading to lower levels of chimeric competency. The barriers that need to be addressed include the evolutionary distance between species, stage-matching, temporal and spatial synchronization of developmental timing, interspecies cell competition and the survival of pluripotent stem cells and embryos, compatibility of ligand–receptor signaling between species, and the ethical concerns of forming such models. By overcoming the interspecies chimera barriers and creating highly competent chimeras, the technology of organ and cellular generation can be honed and refined to develop fully functioning exogenic organs, tissues, and cells for transplantation.

Recent advances in biomedical technologies have extended the boundaries of previously established regulatory guidelines pertaining to stem cell research. These guidelines constrained the study of human pluripotent stem cells (hPSCs) and their derivatives from use under various conditions, including the introduction of hPSCs into the brains of host animals because of concerns of humanizing the brains of animal species. Other guidelines constrained the use of hPSCs in creating human-animal chimeras because of the potential contribution of human stem cells not only to the brain but also to the germline. Some regulatory guidelines forbid the growing of human embryos ex vivo beyond the stage of primitive streak development because of concerns regarding the creation of human forms of life ex vivo. At the subcellular level, there are guidelines regulating the transfer of mitochondria within human embryos. At the molecular level, there are guidelines regulating genome editing to prevent permanent genetic alterations in germline cells. These and other issues related to stem cells have been reviewed, and new research guidelines established by the International Society for Stem Cell Research (ISSCR) for its membership. Because many of the recommended changes by the ISSCR impact research being conducted by members of the American Society for Neural Therapy and Repair (ASNTR), the ASNTR established a task force to review relevant recommendations by the ISSCR to determine which new guidelines to adopt for research conducted by the ASNTR society membership. The final ASNTR recommendations are presented in this document.