Advances in human stem cell therapies:pre-clinical studies and the outlook for central nervous system regeneration

Cell transplantation has come to the forefront of regenerative medicine alongside the discovery and application of stem cells in both research and clinical settings.There are several types of stem cells currently being used for pre-clinical regenerative therapies,each with unique characteristics,benefits and limitations.This brief review will focus on recent basic science advancements made with embryonic stem cells and induced pluripotent stem cells.Both embryonic stem cells and induced pluripotent stem cells provide platforms for new neurons to replace dead and/or dying cells following injury.Due to their capacity for reprogramming and differentiation into any neuronal type,research in preclinical rodent models has shown that embryonic stem cells and induced pluripotent stem cells can integrate,survive and form connections in the nervous system similar to de novo cells.Going forward however,there are some limitations to consider with the use of either stem cell type.Ethically,embryonic stem cells are not an ideal source of cells,genetically,induced pluripotent stem cells are not ideal in terms of personalized treatment for those with certain genetic diseases the latter of which may guide regenerative medicine away from personalized stem cell based therapies and into optimized stem cell banks.Nonetheless,the potential of these stem cells in central nervous system regenerative therapy is only beginning to be appreciated.For example,through genetic modification,stem cells serve as ideal platforms to reintroduce missing or downregulated molecules into the nervous system to further induce regenerative growth.In this review,we highlight the limitations of stem cell based therapies whilst discussing some of the means of overcoming these limitations.

The therapeutic potential of targeting exchange protein directly activated by cyclic adenosine 3',5'-monophosphate(Epac)for central nervous system trauma

Millions of people worldwide are affected by traumatic spinal cord injury,which usually results in permanent sensorimotor disability.Damage to the spinal cord leads to a series of detrimental events including ischaemia,haemorrhage and neuroinflammation,which over time result in further neural tissue loss.Eventually,at chronic stages of traumatic spinal cord injury,the formation of a glial scar,cystic cavitation and the presence of numerous inhibitory molecules act as physical and chemical barriers to axonal regrowth.This is further hindered by a lack of intrinsic regrowth ability of adult neurons in the central nervous system.The intracellular signalling molecule,cyclic adenosine 3′,5′-monophosphate(cAMP),is known to play many important roles in the central nervous system,and elevating its levels as shown to improve axonal regeneration outcomes following traumatic spinal cord injury in animal models.However,therapies directly targeting cAMP have not found their way into the clinic,as cAMP is ubiquitously present in all cell types and its manipulation may have additional deleterious effects.A downstream effector of cAMP,exchange protein directly activated by cAMP 2(Epac2),is mainly expressed in the adult central nervous system,and its activation has been shown to mediate the positive effects of cAMP on axonal guidance and regeneration.Recently,using ex vivo modelling of traumatic spinal cord injury,Epac2 activation was found to profoundly modulate the post-lesion environment,such as decreasing the activation of astrocytes and microglia.Pilot data with Epac2 activation also suggested functional improvement assessed by in vivo models of traumatic spinal cord injury.Therefore,targeting Epac2 in traumatic spinal cord injury could represent a novel strategy in traumatic spinal cord injury repair,and future work is needed to fully establish its therapeutic potential.

Human induced pluripotent stem cell-derived therapies for regeneration after central nervous system injury

In recent years,the progression of stem cell therapies has shown great promise in advancing the nascent field of regenerative medicine.Considering the non-regenerative nature of the mature central nervous system,the concept that“blank”cells could be reprogrammed and functionally integrated into host neural networks remained intriguing.Previous work has also demonstrated the ability of such cells to stimulate intrinsic growth programs in post-mitotic cells,such as neurons.While embryonic stem cells demonstrated great potential in treating central nervous system pathologies,ethical and technical concerns remained.These barriers,along with the clear necessity for this type of treatment,ultimately prompted the advent of induced pluripotent stem cells.The advantage of pluripotent cells in central nervous system regeneration is multifaceted,permitting differentiation into neural stem cells,neural progenitor cells,glia,and various neuronal subpopulations.The precise spatiotemporal application of extrinsic growth factors in vitro,in addition to microenvironmental signaling in vivo,influences the efficiency of this directed differentiation.While the pluri-or multipotency of these cells is appealing,it also poses the risk of unregulated differentiation and teratoma formation.Cells of the neuroectodermal lineage,such as neuronal subpopulations and glia,have been explored with varying degrees of success.Although the risk of cancer or teratoma formation is greatly reduced,each subpopulation varies in effectiveness and is influenced by a myriad of factors,such as the timing of the transplant,pathology type,and the ratio of accompanying progenitor cells.Furthermore,successful transplantation requires innovative approaches to develop delivery vectors that can mitigate cell death and support integration.Lastly,host immune responses to allogeneic grafts must be thoroughly characterized and further developed to reduce the need for immunosuppression.Translation to a clinical setting will involve careful consideration when assessing both physiologic and functional outcomes.This review will highlight both successes and challenges faced when using human induced pluripotent stem cell-derived cell transplantation therapies to promote endogenous regeneration.