Biology 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

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

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

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

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  -cells (Maehr et al, 2009) Refs in Maehr et al, 2009

The Hematopoietic Stem Cell

Cell Fusion From Vassilopoulos and Russell, 2003

A Clone of Xenopus laevis Frogs

The Cancer Stem Cell Hypothesis From Donnenberg and Donnenberg, 2005