Advancing stem cells: New therapeutic strategies for treating central nervous system disorders

In this special issue, we explore new methods and knowledge to improve stem cell transplantation in diseases and conditions such as stroke, PD, and depression. Advancing the conventional idea regarding cell replacement in stem cell therapy, stem cells may also transfer healthy mitochondria to diseased ischemic neurons in stroke and improve the therapeutic time window of tissue plasminogen activator (tPA) in a conjunctive therapy for stroke, and human Wharton\u2019s Jelly-derived mesenchymal stromal cells (hWJ-MSCs) may rely mainly on trophic factor secretion to induce neuroprotective effects. In addition, trophic factors such as neurotrophin-4/5 (NT-4/5) and glial cell line-derived neurotrophic factor (GDNF) may enhance stem cell survival and differentiation to dopaminergic neurons for PD treatment, while encapsulating mesenchymal stem cells and GDNF-secreting cells may increase graft survival rates and their ability to promote neurogenesis and neurotrophic factor secretion in therapies for depression and PD. Of note, transfecting stem cells with a contrast agent such as a superparamagnetic iron oxide (SPIO) for tracking with magnetic resonance imaging (MRI) after transplantation may render these transplanted cells more vulnerable to toxicity in ischemic and hypoxic conditions. Moreover, other methods such as transient microglia depletion may protect against cosmic radiation-induced cognitive impairments, and focusing on the collaborative efforts between oligodendrocytes and the neurovascular unit cells to repair damaged white matter may improve therapies for white matter injury

Translating intracarotid artery transplantation of bone marrow-derived NCS-01 cells for ischemic stroke: Behavioral and histological readouts and mechanistic insights into stem cell therapy

The present study used in vitro and in vivo stroke models to demonstrate the safety, efficacy, and mechanism of action of adult human bone marrow-derived NCS-01 cells. Coculture with NCS-01 cells protected primary rat cortical cells or human neural progenitor cells from oxygen glucose deprivation. Adult rats that were subjected to middle cerebral artery occlusion, transiently or permanently, and subsequently received intracarotid artery or intravenous transplants of NCS-01 cells displayed dose-dependent improvements in motor and neurological behaviors, and reductions in infarct area and peri-infarct cell loss, much better than intravenous administration. The optimal dose was 7.5 × 106 cells/mL when delivered via the intracarotid artery within 3 days poststroke, although therapeutic effects persisted even when administered at 1 week after stroke. Compared with other mesenchymal stem cells, NCS-01 cells ameliorated both the structural and functional deficits after stroke through a broad therapeutic window. NCS-01 cells secreted therapeutic molecules, such as basic fibroblast growth factor and interleukin-6, but equally importantly we observed for the first time the formation of filopodia by NCS-01 cells under stroke conditions, characterized by cadherin-positive processes extending from the stem cells toward the ischemic cells. Collectively, the present efficacy readouts and the novel filopodia-mediated mechanism of action provide solid lab-to-clinic evidence supporting the use of NCS-01 cells for treatment of stroke in the clinical setting

Protein kinase CK2: Systematic relationships with other posttranslational modifications

© Springer International Publishing Switzerland 2015. A wealth of biochemical and genetic evidence has demonstrated that protein kinase CK2 has critical roles in the regulation and execution of numerous biological processes. Large-scale proteomic and phosphoproteomics studies have further reinforced the widespread impact of CK2 on cellular events through interactions with many cellular proteins or protein complexes and through phosphorylation of a vast number of cellular proteins. Given its global participation in many fundamental processes, it is not surprising that CK2 has been implicated in numerous human diseases, a factor that has spurred interest in CK2 as a candidate for molecular- targeted therapy. Despite this growing profile, many questions regarding its precise mechanisms of regulation remain. In fact, several lines of evidence suggest that CK2 is constitutively active, leading to a speculation that CK2 is an unregulated enzyme. Accordingly, there is an apparent paradox that leads to the question of how an unregulated enzyme such as CK2 can be a participant in regulatory processes. In an effort to resolve this paradox, studies in our lab and others have focused on an investigation of the relationships between CK2 and other cellular pathways. Using a combination of computational predictions and database mining together with proteomic strategies and biochemical assays, we have been elucidating systematic relationships between CK2 and regulatory pathways where CK2 phosphorylation sites overlap other posttranslational modifications. Overall, these studies suggest intriguing mechanisms by which CK2 can participate in regulatory events and also how alterations in CK2 levels that accompany disease may promote pathological rewiring of regulatory pathways