1. Biology 624 - Developmental Genetics
Lecture #5 - Stem Cells

2. DEFINITION OF A STEM CELL:
Self-renewing - can give rise to daughter cells that are stem cells
Give rise to differentiated progeny - daughter cells can also differentiate, usually into multiple lineages

3. TYPES OF STEM CELLS:
Embryonic stem cells
Adult stem cells
Cancer stem cell
Germline stem cell
iPS – induced pluripotent stem cells

4. Sources of Pluripotent Stem Cells
Figures\Chapter21\DevBio7e21221.jpg
Adult somatic cells + 4 genes

5. Mouse Embryonic Cells and Derivation of ES Cells
From Keller, 2005

6. 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

7. Hematopoietic stem cells – first identified
adult stem cells

8. Some types and sources of adult stem cells
From Jordan et al, 2006

9. 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)

10. The stem cell niche concept
From He et al, 2009

11. Blood vessels may provide a neural stem cell niche
Kokovay et al (2010) Cell Stem Cell

12. Adult Stem Cells - Outstanding Issues
How are niches set up and maintained?
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?

13. The Cancer Stem Cell Hypothesis
Cancers are heterogeneous – not all cells
have the same markers, behaviors – how arise?
Does this reflect “potential”? Do some
cells maintain or acquire stem cell properties
and populate the rest of the tumor with non-
tumorigenic cells?
If so there should be a hierarchy of cells –
and this has implications for therapy

14. The Cancer Stem Cell Hypothesis
From Dick, 2008

15. Scenarios of how cancer stem cells can affect tumor formation
From Jordan et al, 2006

16. The Cancer Stem Cell Hypothesis –
Outstanding Issues
Can clonal evolution explain the data?
Is it a global model (ie all cancers) or
restricted? If restricted, how?
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

17. Alternate cancer stem cell hypothesis: 1. Niche requirements change 2
Alternate cancer stem cell hypothesis: 1. Niche requirements change 2. Progenitors mutate to self-renew
From Lobo et al, 2007

18. Myeloid Dysplasia/Leukemia via a Mutation in the Niche…
Raaijmakers et al, 2010

19. Can we make stem cells from cells that are NOT stem cells –
i.e. “run the tape backwards”?

20. Successful Nuclear Transplants as a Function of the Developmental Age of the Donor Nucleus
Figures\Chapter04\DevBio7e04060.jpg

21. Cloned Mammals, Whose Nuclei Came From Adult Somatic Cells
Figures\Chapter04\DevBio7e04081.jpg

22. Figures\Chapter04\DevBio7e04082.jpg

23. Figures\Chapter04\DevBio7e04083.jpg

24. Embryonic Stem Cell Therapeutics
Blood Vessel
Precursors
Figures\Chapter21\DevBio7e21231.jpg

25. Embryonic Stem Cell Therapeutics
Figures\Chapter21\DevBio7e21232.jpg

26. iPS suggest an alternative source of stem cells
From Nishikawa et al, 2008

27. Comparison of protocols to derive pluripotent stem cells
From Nishikawa et al, 2008

28. How iPS might help therapeutically
From Nishikawa et al, 2008

29. 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)
Type I diabetes – differentiate into pancreatic b-cells (Maehr et al, 2009)
Refs in Maehr et al, 2009

30. Wu and Hochedlinger, 2011

32. The Hematopoietic Stem Cell
Figures\Chapter15\DevBio7e15211.jpg

33. From Vassilopoulos and Russell, 2003
Cell Fusion
From Vassilopoulos and Russell, 2003

34. A Clone of Xenopus laevis Frogs
Figures\Chapter04\DevBio7e04070.jpg

35. The Cancer Stem Cell Hypothesis
From Donnenberg and Donnenberg, 2005

36. Hematopoietic stem cells – first identified
adult stem cells
Figures\Chapter15\DevBio7e15212.jpg