Stem Cells and Differentiation Part II PDF

Stem Cells and Differentiation Part II Copyright and Disclosure All materials found on GCSoM’s course and project sites may be subject to copyright protection and are restricted from further dissemination, retention, or copying. I have no financial relationship with a c...

Stem Cells and Differentiation Part II Copyright and Disclosure All materials found on GCSoM’s course and project sites may be subject to copyright protection and are restricted from further dissemination, retention, or copying. I have no financial relationship with a commercial entity producing health care related products and/or service  Learning Objectives define the stem cell niche understand differentiation, terminal differentiation, and dedifferentiation, give examples of each, and understand how these processes are controlled identify errors of differentiation  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 self- differentiati renewal on Stem cell Growth factors, cell signaling factors 3  Cell Differentiation: Differential Gene Expression Another example: all of the intestinal cell types derived from differentiation of Lg5+ CBC intestinal stem cells http://ib.bioninja.com.au/standard-level/topic-1-cell-biology/11-introduction-to-cells/cell-differentiation.html 4  Differentiation: Importance of Signaling Pathways 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 Image by cybertory - http://en.wikipedia.org/wiki/File:Signa expression l_transduction_v1.png, CC BY-SA 3.0, https://commons.wikimedia.org/w/ind ex.php?curid=12081090 5  Differentiation: Importance of Epigenetic Controls 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. Thus, 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 those genes required for the specialized cell phenotype and function are expressed. On the other hand, the more “potent” the stem cell, the more it is expected that a greater number of genes are potentially expressed. 6  Intestinal Epigenetics In the intestines, epigenetic changes can be more subtle. The overall chromatin structure can be similar between crypt and villus cells but in each compartment, specific genes can be modulated by epigenetic modifications (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 7  Terminal Differentiation “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): “Cells in hematopoietic and epithelial lineages maintain tissue homeostasis by a dynamic equilibrium balancing cell proliferation and cell death. Cell death in these lineages has been recognized as apoptotic and generally occurs after a terminal differentiation event.” from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2138196/ Terminal differentiation therapy: “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/ 8  Dedifferentiation Can Replace Lost Stem Cells The Intestinal Example – Replacing the Loss of Lgr5+ CBC Cells Replacement of lost Lgr5-positive stem cells through plasticity of their enterocyte-lineage daughters http://www.cell.com/cell-stem-cell/pdf/S1934-5909(16)00002-3.pdf In this article, Tetteh et al. show that enterocyte-lineage progenitors can become stem cells during intestinal regeneration. Additionally, 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. 9  Putting It Together 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 10