Current Stem Cell Research & Therapy - Volume 7, Issue 6, 2012

The past decade has witnessed numerous publications on mesenchymal stem cells (MSC), which have great potential in regenerative medicine. MSC from various types of origins exhibit different characteristics, which may relate to the maintenance role of MSC in that specific source. Reports have emerged that among the most widely investigated sources, umbilical cord (UC) or umbilical cord blood (UCB) derived MSC throw advantages over bone marrow (BM) derived MSC due to their close to fetal origin. Here the methodologies used to separate MSC from UC or UCB, and the intrinsic properties, including proliferation capacity, multipotency, cytokine profile, cell surface protein expression and gene expression, between UC, UCB and BM derived MSC, are discussed in details, though may not in a full picture, for the first time.

The alternative splicing of precursor mRNA is an essential mechanism for protein diversity. It plays important biological roles, such as proliferation, differentiation and development of cells. Furthermore, alternative splicing participates in the pathogenesis of diseases, including cancer. Thus, in-depth understanding of splicing regulation is of great significance. Regulation of alternative splicing is an extraordinary complicated process in which several signal molecules are at work. Besides the cis-elements and trans-factors, several lines of evidences suggest that other molecules, structures or process also regulate splicing, such as RNA structures, transcription and transcription factors, chromatin and protein. Meanwhile, increasing body of evidence shows that alternative splicing correlated closely to stem cell lineage differentiation. It means that there is a fundamental role for splicing in controlling regulatory program required for cell lineage differentiation. This review systematically sums up the regulation of alternative splicing and summarizes the splicing events during cell lineage differentiation of stem cells.

Despite updating knowledge and a growing number of medications for multiple sclerosis (MS), no definite treatment is available yet for patients suffering from progressive forms of the disease. Autologous bone marrow derived mesenchymal stem cell (BM-MSC) transplantation is a promising method proposed as a therapy for MS. Although the safety of these cells has been confirmed in hematological, cardiac and inflammatory diseases, its efficacy in MS treatment is still under study. Patients with progressive MS (expanded disability status scale score: 4.0 –6.50) unresponsive to conventional treatments were recruited for this study. Twenty-five patients [f/m: 19/6, mean age: 34.7±7] received a single intrathecal injection of ex-vivo expanded MSCs (mean dose: 29.5×106 cells). We observed their therapeutic response for 12 months. Associated short-term adverse events of injection consisted of transient low-grade fever, nausea /vomiting, weakness in the lower limbs and headache. No major delayed adverse effect was reported. 3 patients left the study for personal reasons. The mean (SD) expanded disability status scale (EDSS) score of 22 patients changed from 6.1 (0.6) to 6.3 (0.4). Clinical course of the disease (measured by EDSS) improved in 4, deteriorated in 6 and had no change in 12 patients. In MRI evaluation, 15 patients showed no change, whereas 6 patients showed new T2 or gadolinium enhanced lesions (1 lost to follow-up). It seems that MSC therapy can improve/stabilize the course of the disease in progressive MS in the first year after injection with no serious adverse effects. Repeating the study with a larger sample size, booster injections and longer follow-up using a controlled study design is advised.

Cancer stem cell-like cells (CSCs) are cancer cells that have the ability of self-renewal and differentiation into multiple malignant cell types (hierarchy). Thus, can cause relapses and metastasis. CSCs' phenotype is defined by special transcription factors such as Nanog, Oct3/4, Sox2, Nestin, and CD34. The present study aims to determine the change in gene expression of the above markers in correlation with the stage of the disease in breast cancer patients. Initially, whole blood samples from patients with breast cancer were collected, followed by the isolation and culture of circulating tumor cells (CTCs). This was followed by the quantification of CSCs from the above cultures. CSCs' molecular analysis was performed with qPCR, with the use of gene specific primers. At the same time of the analysis, the clinical assessments of the patients were requested from their physicians. The results indicated a linear relationship between the gene expression of stemness markers and the stage of the disease, as well as specific expression patterns by stage. It seems that these genes have an important role in the progression of the disease, thus they might be target for new treatment approaches.

This review focuses on gene transcription patterns of leukemogenic S-phases in mitotic cell cycles for identification of enzymatic reactions as potential targets for epigenetics-based drug therapy. Transcription of leukemic genes is triggered by reprogrammed transcription factors (TFs) mediated by chromatin histones. Reprogrammed TFs originate from transcriptional alterations of CpG methylation patterns of mutated epigenetic genes. They preserve memory information of earlier leukemogenic exposures, even transgenerationally via the zygote, through small (e.g. pi)RNA transmitted between cells by exosomes. Normally, reprogrammed TFs are enzymatically silenced and stored as markers in heterochromatic domains. Failure of intra S-phase surveillance (IS) permits the formation and continual operation of DNA replication forks in spite of persisting genotoxic stress. Silenced TFs are re-activated by euchromatin, most likely through leakages of insulator barriers of cis-regulating chromatin modulators (CRM) that normally separate hetero- from euchromatin domains. During transport by sliding nucleosomes, reprogrammed leukemogenic TFs are misplaced at transcription factor binding-/starting-sites (TFBS /TSS) allowing them to interact with and trigger replication of mutated leukemic genes. In conclusion: Interactions of enzymatically reprogrammed TFs, transcribed from mutated epigenetic genes, with replicating leukemic genes at TFBS/TSSs are key driving forces in leukemogenesis. Probably, epigenetic genes, although mutated, still retain their control of replication of leukemic genes. Epigenetics-based enzyme inhibitors must target reprogrammed TFs. Prudently, therapeutic corrections should be introduced within the frame of conventional, cytoreductive treatment protocols. Alternatively, reprogrammed TFs could be replaced by cell populations with regular TF production. Clinically, classification of leukemias should be based on their epigenetic presentation.

The field of regenerative medicine (RM), encompassing stem cell (SC) technologies, therapeutics, tissue engineering (TE), biomaterials, scaffolds and other enabling technologies provides a wide gamut of tools and tracks to combat, manage and hopefully cure serious human and animal injuries, dysfunctions and diseases. This review illustrates the trends that are becoming the major platforms in this field. The last 10 years in itself has seen major definitive observations, including multi-track directives of adult stem cell translational technologies, tissue and organ engineering protocols, iPS cell applications and understanding of the role of cancer stem cells to develop effective anti-cancer regimens. With the rapid advances of RM translational research, further advances are expected to be implemented for personalized repair and curative outcomes. RM future is bright although laden with challenges of global fragmentation which needs coherent consolidation, stringent cost and time effective regulation and long-term funding mechanisms, so clinical and diagnostic solutions are realized and recognized to combat unmet medical needs.