Abstract
D. J. Eve
Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA
Every year, the American Society for Neural Therapy and Repair features a wide diversity of subjects, providing an insight into current research trends in regenerative medicine. In 2014, Parkinson's disease—related presentations were again the most popular topic, with traumatic brain injury, spinal cord injury, and stroke being close behind. Other disorders included Huntington's disease, brain cancer, and bipolar disorders. Several studies related to multiple diseases. An increasing proportion of presentations related to stem cells, with the study of multiple stem cell types being the most common. This meant that again, overall, the neural stem cell was the most frequently studied stem cell type. Induced pluripotent stem cells were increasingly popular, including two presentations each on a muscle-derived dedifferentiated cell type and cells derived from bipolar patients. More than 55% of the stem cell studies involved transplantation, with human-derived cells being the most frequently transplanted, while rats were the most common recipient. Two human autologous studies for spinal cord injury and hypoxia-derived encephalopathy, and a further three allogenic studies for stroke and spinal cord injury, were also featured. This year's meeting highlights the increasing promise of stem cells and other therapies for the treatment of neurodegenerative disorders.
D. J. Eve, P. R. Sanberg, and C. V. Borlongan
Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA
The importance of gender with regard to both disease susceptibility and potential therapeutics has classically been severely overlooked. It is now clear that cells taken from a male respond in different ways to stimuli than those from females. A search of the recent literature reveals a number of studies highlighting these differences and how they may relate to disease and/or therapies. Some of these are summarized below. In general, female cord blood has a higher total nucleated cell count (but lower CD34+ cell count) than that of the male, which may mean that cord blood from one gender may be more beneficial than the other, depending on the therapeutic cells of interest. Estrogen has been shown to promote hematopoietic stem cell proliferation in females (but not males), while the ability of bone marrow mesenchymal stem cells to undergo osteogenic differentiation appears to be less than in males in mice. The presence of specific variants of the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) gene has been shown to lead to an earlier age of onset for Huntington's disease and amyotrophic lateral sclerosis in males, but not in females, while ApoE4 appears to slightly decrease lifespan in general and increase the incidence of Alzheimer's disease in females. Differences between escape latency and target quadrant duration in the Morris water maze have also been detected in the female outbred Institute of Cancer Research mouse compared with those of the male. The recent literature helps to illuminate the importance of considering the gender of the patient with regard to disease and therapy and, in transplantation studies, the gender of both the donor and the recipient.
T. T. Lah,*† H. Motaln,* and H. Ulrich†
*Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
†Institute of Chemistry, University of Sao Paolo, Brazil
Migration of mesenchymal stem cells (MSCs) from the blood and/or bone marrow (BM) to the tumor site has been demonstrated in vivo, including for glioblastoma (GBM). However, the outcome of GBM cell interactions with MSCs is still poorly understood, although it is highly relevant for understanding glioma progression and therapy. We aimed to investigate (1) indirect interactions of BM-MSCs and GBM cells under in vitro conditions and (2) the direct interactions in cocultures of both types of cells. Four different BM-MSC clones (MSC 1-4) and three different GBM cell lines (U87, U373, U251 lines) were used to study their mutual paracrine interactions in cocultures compared to their monocultures. The mutual effects on cell growth, proliferation, and invasion in Matrigel were quantified. To study their cellular cross-talk, the cytokines were measured by cytokine arrays and by cDNA microarrays in each of the interacting cell types, and analyzed by bioinformatics tools. We demonstrated that paracrine effects via a panel of cytokines released from MSCs are responsible for the impairment of GBM cell invasion and proliferation, as well as for induction of their senescence. On the other hand, U87-MG cells strongly inversely affected growth and invasion of MSCs. Among the chemokines, the chemokine C-C motif ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) was collectively identified as the most significantly upregulated chemokine in the MSC lines, and its role in U87-MG invasion was functionally confirmed. We proposed (Motaln et al., Cell Transplant.21:1529-1545; 2012) a novel mechanism of CCL2/MCP-1 antimigratory effects on GBM cells, distinct from its immunomodulatory role. When cells directly interact, they form cell-cell contact, for example, the functional synctitium (Schichor et al., Exp. Neurol. 234:208-219; 2012), which resulted in both decreased GBM proliferation but increased invasion, which contrasts with the effects of indirect cocultures. Carbonic anhydrase IX and bradykinin receptor 1 (BDKR1) emerged as the two most differentially expressed factors in direct cell contact. Further investigations using bioinformatics and functional validations of these, and a cohort of other migration-associated genes, in GBM cells are in progress. These may reveal paradoxical effects of BM-MSCs, which directly increase GBM cell migration, but also secrete cytokines that impair and keep the tumor cells in their distant vicinity. Consideration of significant alterations in the GBM phenotype in the presence of MSCs, as reported here, is urgently needed when designing MSC-based cell therapies for fatal cancers such as GBM.
A. J. Smith,* S.-H. Kim,* N. K. Duggirala,† J. Jin,‡ L. Wojtas,† J. Ehrhart,§ B. Giunta,‡ J. Tan,¶ K. B. Sneed,# P. R. Sanberg,* C. V. Borlongan,* M. J. Zaworotko,† and R. D. Shytle*
*Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA
†Department of Chemistry, College of Arts and Sciences, University of South Florida, Tampa, FL, USA
‡Neuroimmunology Laboratory, Department of Psychiatry and Behavioral Neurosciences, University of South Florida Morsani College of Medicine, Tampa, FL, USA
§Saneron CCEL Therapeutics, Inc., Tampa, FL, USA
¶Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry and Behavioral Neurosciences, University of South Florida Morsani College of Medicine, Tampa, FL, USA
#College of Pharmacy, University of South Florida, Tampa, FL, USA
Despite its narrow therapeutic window, lithium is still regarded as the gold standard comparator and benchmark treatment for mania. Recent attempts to find new drugs with similar therapeutic activities have yielded new chemical entities. However, these potential new drugs have yet to match the many bioactivities attributable to lithium's efficacy for the treatment of neuropsychiatric diseases. Consequently, an intense effort for reengineering lithium therapeutics using crystal engineering is currently underway. Our preliminary endeavors to improve the safety and efficacy of lithium therapy using crystal engineering techniques have been encouraging. Unexpectedly, we found a modulated pharmacokinetic profile of lithium by incorporating salicylic acid into the crystal structure. Moreover, we show that this change in speciation did not negatively affect the efficacy of lithium at clinically relevant endpoints including glycogen synthase kinase (GSK)-3β inhibition, neuronal brain-derived neurotrophic factor (BDNF) production, abolishment of nitric oxide production in activated microglia, and the induction of neuronal differentiation in stem cells. Crystal engineering also affords opportunities for the incorporation of additional biologically active components into a new chemical entity that work synergistically at these endpoints. These findings could be critical for the development of the next generation of lithium therapeutics with improved efficacy and safety.