Stem Cells and Differentiation, Part III PDF

Video 43: Stem Cells and Differentiation, Part III Slide 3: Stem cells can be used for therapeutic applications, including those listed here. Slide 4: Parkinson’s disease can be targeted by stem cell therapy, to enhance and/or replace dopamine-producing cells in the brain. Slide 5: Stem cell ther...

Video 43: Stem Cells and Differentiation, Part III Slide 3: Stem cells can be used for therapeutic applications, including those listed here. Slide 4: Parkinson’s disease can be targeted by stem cell therapy, to enhance and/or replace dopamine-producing cells in the brain. Slide 5: Stem cell therapies capable of regenerating any human tissue damaged by injury, disease, or aging could be available within a few years, following landmark research led by UNSW Australia researchers. Slide 6: Many methodological difficulties need to be worked out, e.g., delivery. There are moral debates about embryonic stem cells: social and political implications. IPS cells need more work to be effective and safe. Immune rejection. Adult stem cells – mutations? Cancer? Not as “potent”. But if they are the patient’s cells, then there is no immune rejection problem. But successes exist, such as the relatively common use of bone marrow transplantation Slide 7: Errors of differentiation include: Dysplasia is the abnormal arrangement of cells, can be harmless or precursor to cancer. Metaplasia is the conversion of one cell type to another (typically at the stem cell level), often seen with tissue damage and extensive regeneration. Anaplasia is the loss of differentiation, typically seen in cancer. It is expected that changes in gene expression accompany these alterations, some with a causative correlation. Slide 8: Cancer stem cell hypothesis: most cancers are driven by a subset of cells in the tumor that have stem cell-like properties and give rise to the general mass of the tumor. These cells, called cancer stem cells, are typically more resistant to standard cancer therapy. If the bulk of the tumor is eliminated, but the cancer stem cells remain, they can cause the reformation of the tumor. Is cancer recurrence after therapy caused by these cells? If yes, then the elimination of these cells is critical for cancer therapy. Cancer stem cells may originate from stem cells that acquire oncogenic mutations and/or from mature cells that acquire oncogenic mutations and then dedifferentiate into cancer stem cells. The dedifferentiation possibility means that ALL cancer cells must be eliminated, not just the cancer stem cells since any remaining “mature” cancer cells may give rise to cancer stem cells. Slide 9: Likely, both transformed stem cells and transformed progenitor cells can contribute to cancer, in a context-dependent manner. Context can include tissue/organ site of cancer. Slide 10: Dedifferentiation can occur in cancer. If you remove the cancer stem cells but leave other cancer cells behind, these other cells can dedifferentiate into cancer stem cells. Cell-type plasticity within a tumor has recently been suggested to cause a bidirectional conversion between tumor-initiating stem cells and non-stem cells triggered by an inflammatory stroma. Thus, elevated NF-κB signaling enhances Wnt activation and induces dedifferentiation of non-stem cells that acquire tumor-initiating capacity. Therefore, data support the concept of bidirectional conversion and highlight the importance of inflammatory signaling for the dedifferentiation and generation of tumor-initiating cells in vivo. The conclusion is that the therapy needs to eliminate all types of cancer cells. Slide 11: EMT and metastasis can be associated with cancer stem cells. Epithelial- mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are processes that normally occur in embryogenesis. However, these processes are “hijacked” in cancer. Cancer cells, possibly cancer stem cells, undergo EMT, through the action of Wnt signaling and other cell signaling pathways, ZEB transcription factors, SLUG, and other factors. In EMT, the cells become more mesenchymal, invasive, and non-proliferative in phenotype. They can metastasize to other sites. At these new sites (distant organs and tissues), the cells undergo MET, become more epithelial again, and proliferate to form metastatic tumors at the new sites. Slide 12: There is an association between stem cell divisions and cancer risk. Tissues with a greater number of stem cell divisions in a lifetime tend to have a higher risk of developing cancer. This is consistent with the cancer stem cell hypothesis and even more consistent with the general idea that more divisions, more cells, and more proliferative tissue gives a greater probability of developing neoplastic cells. If the mutation rate per division is approximately the same between tissues, then more divisions will give more mutations. Slide 13: Stem cells are related to aging. Recent data suggest that we age, in part, because our self-renewing stem cells grow old as a result of heritable intrinsic events, such as DNA damage, as well extrinsic forces, such as changes in the supporting niches. Slide 14: Fundamental points. Stem cells can be used for therapeutic applications; there are some methodological difficulties and some successes. Errors of differentiation, some of which can lead to cancer, include dysplasia, metaplasia, and anaplasia. Cancer stem cells can drive tumor formation, cause recurrence, be involved in metastasis (EMT), and can sometimes result from dedifferentiation. Cancer risk is related to the number of stem cell divisions. Stem cells are related to aging.