Towards functional regeneration of the central nervous system: Glial calcium signaling in reactive gliosis and the therapeutic potential of bone marrow -derived mesenchymal stem cells for retinal degenerative diseases.

摘要

While great strides have been made in medicine and technology in the recent decades, satisfactory treatment of injuries and diseases in the central nervous system remain largely elusive. Neurodegenerative disorders such as Alzheimer's and Parkinson's disease as well as degenerative retinal disorders such as Age-related macular degeneration and Retinitis pigmentosa are devastating illnesses that severely affect the quality of life of patients and current therapies for them are at best symptomatic treatments. It is no doubt that effective therapeutic strategy for these diseases will require thorough knowledge of the pathogenesis of the diseases as well as development of the central nervous system to not only halt the progression of the degeneration but also repair the loss or dysfunctional tissue in order to restore cognitive functions.;Stem cells have roused great enthusiasm in recent years due to their therapeutic potential to restore function by replacing the lost or dysfunctional cell types. Bone marrow-derived mesenchymal stem cells (BMSCs) are of particular interest as somatic (adult) stem cells because of its relative ease of isolation and the minimal ethical concerns associated with its use. Numerous studies have suggested the potential of bone marrow-derived mesenchymal stem cells (BMSCs) to differentiate into cell types of all three germ layer. However, as is common with most fast growing research fields, its rapid progress to yield clinical treatments leaves many fundamental questions unanswered. Amongst them, large variations in experimental protocols make comparison of findings between different studies particularly difficult. In the studies presented here, we compare the viability and differentiation potential of BMSCs on standard surface chemistries and report the optimum growth conditions of these cells for neuronal differentiation as well as induction of neural progenitor marker in BMSCs.;In addition, recent studies in neurobiology have revealed significant functional roles of glial cells in regulating synaptic activity and information processing that were previously unappreciated. Specifically, calcium signaling has been highlighted as a potential mechanism of intra- and intercellular communication in networks of neurons and glia that is not only essential in normal physiology but may also play crucial roles in progression of degeneration in disease via processes mediated by the glia. In the studies presented here, we investigate the role of glial calcium signaling in reactive gliosis, an endogenous inflammatory response of the CNS to injury and disease that often aggravates the loss function and hampers effectively recovery. We introduce the rMC-1 Muller glia cell line as a model for studying calcium signaling and present evidence for complex signaling dynamics in intercellular calcium transient propagation within glial networks that may be altered under pathological conditions. In addition, we show that disruption of glial calcium homeostasis via altered calcium signaling dynamics directly correlates with known hallmarks of reactive astrogliosis and may play an important role in pathogenesis of neurodegenerative disease.