1!Biology 624 - Developmental Genetics!Lecture #7 - Stem Cells !DEFINITION OF A STEM CELL:!1. Self-renewing - can give rise to daughter cells that are stem cells!2. Give rise to differentiated progeny - daughter cells can also differentiate, usually into multiple lineages!3. Cells can efflux (transport out of the cell) various dyes, etc! --allow for sorting by FACS (side population)! --may be why cancer comes back after chemo !TYPES OF STEM CELLS:!1. Embryonic stem cells!2. Adult stem cells!3. Cancer stem cell!4. Germline stem cell!5. iPS – induced pluripotent stem cells!Sources of Pluripotent Stem Cells!Adult somatic cells + 4 genes!Mouse Embryonic Cells and Derivation of ES Cells!From Keller, 2005 !ES Cells Maintain Pluripotency by!Inhibiting Differentiation!--Oct4/Sox2/Nanog +!PcG genes block diff!genes!-- LIF and BMP block!diff via inhibit MAPK!--FGF promote diff!From He et al, 2009 !2!Hematopoietic stem cells – first identified"adult stem cells!Some types and sources of adult stem cells!From Jordan et al, 2006 !ADULT STEM CELLS:!--HSC = Hematopoietic system!--Neural stem cells = Neurons and glia!--Gut stem cells = gut epithelium and other cells!--Breast stem cells = mammary glands!-- Mesenchymal stem cells? = numerous mesodermal derivatives!-- Satellite cells in muscle? = muscle!-- Liver stem cells?!The stem cell niche concept!From He et al, 2009 !Adult Stem Cells - Outstanding Issues!1. How are niches set up and maintained?!2. Mechanism(s) of age-related loss of !stem cells – “used up” vs. niche loss !3. Role in cancer – do they mutate to cancer!stem cells?!The Cancer Stem Cell Hypothesis!1. Cancers are heterogeneous – not all cells!have the same markers, behaviors – how arise?!2. Does this reflect “potential”? Do some!cells maintain or acquire stem cell properties!and populate the rest of the tumor with non-!tumorigenic cells?!3. If so there should be a hierarchy of cells – !and this has implications for therapy !3!The Cancer Stem Cell Hypothesis!From Dick, 2008 !Scenarios of how cancer stem cells can affect tumor formation!From Jordan et al, 2006 !The Cancer Stem Cell Hypothesis –!Outstanding Issues!1. Is it a global model (ie all cancers) or !restricted? If restricted, how?!2. Genetic vs. epigenetic – if cancer stem!cells contribute to a tumor, how labile?!3. The role of the “stem cell niche” in cancer!stem cell biology!Alternate cancer #stem cell hypothesis:#1. Niche requirements#change#2. Progenitors mutate#to self-renew!From Lobo et al, 2007 !Can we make stem cells from!cells that are NOT stem cells –!i.e. “run the tape backwards”?!Successful Nuclear Transplants as a Function of the"Developmental Age of the Donor Nucleus!4!Cloned Mammals, Whose Nuclei Came From Adult Somatic Cells!Embryonic Stem Cell Therapeutics!Blood Vessel!Precursors!Embryonic Stem Cell Therapeutics!From Nishikawa et al, 2008!iPS suggest an alternative source of stem cells !5!From Nishikawa et al, 2008!Comparison of protocols to derive pluripotent stem cells!From Nishikawa et al, 2008!How iPS might help therapeutically! iPS from patients with diseases have been generated!1. ALS – differentiate to motor neurons (Dimos et al, 2008)!2. Parkinson’s disease (Soldner et al, 2009)!3. Type I diabetes – differentiate into pancreatic β-cells (Maehr et al, 2009)!Refs in Maehr et al, 2009!The Hematopoietic Stem Cell!Cell Fusion!From Vassilopoulos and Russell, 2003!6!A Clone of Xenopus laevis Frogs!The Cancer Stem Cell Hypothesis!From Donnenberg and Donnenberg, 2005