Biology 624 - Developmental Genetics

Lecture #5 - 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

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 byInhibiting Differentiation

--Oct4/Sox2/Nanog +PcG genes block diffgenes

-- LIF and BMP blockdiff 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?--Vascular stem cells? (pericytes,

hemangiomas)

The stem cell niche concept

From He et al, 2009

Blood vessels may provide a neural stem cell niche

Kokovay et al (2010) Cell Stem Cell

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 cancerstem cells?

The Cancer Stem Cell Hypothesis

1.Cancers are heterogeneous – not all cellshave the same markers, behaviors – how arise?

2.Does this reflect “potential”? Do somecells maintain or acquire stem cell propertiesand 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.Can clonal evolution explain the data?

2.Is it a global model (ie all cancers) or restricted? If restricted, how?

2.Genetic vs. epigenetic – if cancer stemcells contribute to a tumor, how labile?

3. The role of the “stem cell niche” in cancerstem cell biology

Alternate cancer stem cell hypothesis:

1. Niche requirementschange

2. Progenitors mutateto self-renew

From Lobo et al, 2007

Raaijmakers et al, 2010

Myeloid Dysplasia/Leukemia via a Mutation in the

Niche…

Can we make stem cells fromcells 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 VesselPrecursors

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

Wu and Hochedlinger, 2011

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

Hematopoietic stem cells – first identified

adult stem cells