Stem Cells and Differentiation Part II PDF

Video 42: Stem Cells and Differentiation, Part II Slide 3: What is the stem cell niche? Microenvironment that influences decisions of stem cell maintenance and proliferation (survival and self-renewal) vs. stem cell differentiation Growth factors, cell signaling factors, etc., alt...

Video 42: Stem Cells and Differentiation, Part II Slide 3: What is the stem cell niche? Microenvironment that influences decisions of stem cell maintenance and proliferation (survival and self-renewal) vs. stem cell differentiation Growth factors, cell signaling factors, etc., alter gene expression in the stem cells to affect cell fate Slide 4: Cell differentiation, such as that found in the intestine, or neuronal differentiation, is based upon differential gene expression. Different sets of genes are expressed in stem cells vs. progenitor cells vs. mature cells. All of the intestinal cell types derived from differentiation of Lg5+ CBC intestinal stem cells. Slide 5: Signaling pathways, including those mentioned on this slide, are crucial for inhibiting or promoting differentiation. Tissue-specific gene expression: cell signaling, transcription factors, and epigenetic controls Important signaling pathways for pluripotency and differentiation: IGF, FGF, Wnt, TGF-beta, BMP, Notch Cell signaling: ligands, receptors, downstream consequences — typically involving altered gene expression Slide 6: In addition to, and in conjunction with, differences in cell signaling and transcription factor expression, epigenetic modifications are important for stem cell maintenance or differentiation. For example, increased DNA methylation and increased formation of heterochromatin accompany differentiation. This suggests that as the cell becomes more specialized and loses “stemness”, genes are being inactivated so that only the genes required for the specialized cell phenotype and function are expressed. On the other hand, the more “potent” a stem cell is, the greater number of genes that are potentially expressed. Slide 7: In the intestine, epigenetic changes can be more subtle. The overall chromatin structure can be similar between crypt and villus cells but in each compartment-specific genes might be modulated by epigenetic modifications (e.g., acetylation, methylation). In the differentiated cells, enhancers associated with “stemness” are turned off, while “differentiation” enhancers are turned on. In the intestinal stem cells, enhancers of both secretory and absorptive lineage genes are in a generally active state. Slide 8: The last stage of differentiation is terminal differentiation. What is this? “The terminally differentiated cell, which has a specific function within the organism, will proliferate as only one cell type. These cells express genes that are specific to their cell type and function.” From https://www.qiagen.com/us/shop/genes-and-pathways/complete-biology-list/terminal- differentiation-markers/. Another definition is that terminally differentiated cells are specialized cells that have irreversibly lost the ability to proliferate. However, some terminally differentiated cells can in some contexts proliferate, but not to an extent that significantly contributes to tissue architecture. Apoptosis often follows terminal differentiation (e.g., in the intestine). One anti-cancer therapeutic approach is to induce terminal differentiation of the cancer cells: “Cancer cells often have an immature phenotype representing a block in the normal differentiation pathway. Treatments capable of inducing differentiation have been discovered for cancer cell lines in vitro and have in some cases been developed as anticancer therapies.” From https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2138196/ Slide 9: Replacement of lost Lgr5-positive stem cells through plasticity of their enterocyte-lineage daughters. Reference to article In this article, Tetteh et al. show that enterocyte-lineage progenitors can become stem cells during intestinal regeneration. These cells generate Paneth-like cells and turn on genes that promote recovery from injury. In sum, "stemness" in intestinal crypts is not "hard-wired"; many progenitors can regain stemness upon loss of the actual stem cells  Video 42: Stem Cells and Differentiation, Part II Slide 10: Fundamental points. The stem cell niche helps to control decisions of stem cell proliferation vs. differentiation. Differentiation is controlled by gene expression, cell signaling, and epigenetics. Terminal differentiation is the last step in the differentiation process. Dedifferentiation can occur, altering more differentiated cells (not terminally differentiated ones) into cells with more stem cell- like properties. o Errors of differentiation: Dysplasia – abnormal arrangement of cells, can be harmless or precursor to cancer. Metaplasia – conversion of one cell type to another (typically at the stem cell level), often seen with tissue damage and extensive regeneration. Anaplasia – loss of differentiation, typically seen in cancer.