ANAT3231: lectures overview
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1 ANAT3231: lectures overview Stem Cell Biology Stem Cell Technology Resources: biology/ Essential Cell Biology 3 rd edition Alberts Dr Annemiek Beverdam School of Medical Sciences, UNSW Wallace Wurth Building Room 234 A.Beverdam@unsw.edu.au ANAT3231: lectures overview Stem Cell Biology Tissue homeostasis and regeneration Stem cell biology Stem cell niches Stem cell regulation Stem cells and cancer Dr Annemiek Beverdam School of Medical Sciences, UNSW Wallace Wurth Building Room 234 A.Beverdam@unsw.edu.au 1
2 ANAT3231: lectures overview Stem Cell Technology Regenerative medicine Stem cell sources Stem cell applications Knock out technology CRISPR/CAS9 genome editing Dr Annemiek Beverdam School of Medical Sciences, UNSW Wallace Wurth Building Room 234 Prenatal development 2
3 Tissue homeostasis Tissue renewal in higher vertebrates 3
4 Tissue regeneration Tissue regeneration in higher vertebrates 4
5 Tissue renewal in lower vertebrates and animals Stem cells divide to self renew and to produce terminally differentiated cell types Assymmetric cell division 5
6 Stem cells potential Totipotency: capacity to generate all cell types within the body + extraembryonic tissue Pluripotency: capacity to generate all cell types within the body Multipotency: capacity to give rise to more than 1 cell type Uni-potent stem cell: tissue precursor cells, capacity to give rise to one cell type only Embryonic stem cells 6
7 Adult stem cells Stem cell niche: Keeps stem cells in an undifferentiated state 7
8 Epidermal Stem Cell Niches: Basal Epidermal Stem Cells: 1 month Basal layer Keratinocytes of the interfollicular epidermis 8
9 The Hair Follicle Bulge Stem Cell Niche Epidermal bulge stem cells: hair follicle keratinocytes Melanocyte bulge stem cells: melanocytes The Intestinal Crypts Stem Cell niche Crypt Base Columnar Stem Cells Transit-amplifying cell (Radtke and Clevers, Science 2005) 9
10 The Haemopoietic Stem Cell niche approximately new blood cells are produced daily Bone marrow Blood and tissues HSC: haemopoietic stem cell MPP: multipotent progenitor cell CLP: common lymphoid progenitor CMP: common myeloid progenitor cell GMP: granulocyte/monocyte precursor cell MEP: Megakaryocyte-erythroid precursor cell Figure 5.1. Hematopoietic Stem Cell Differentiation (2001 Terese Winslow, Lydia Kibiuk) Subventricular and Subgranular Zone adult neurogenesis SGZ SVZ Rostral Migratory Stream radial glial cells TA cells neuroblasts post-mitotic excitatory granule cells of dentate gyrus multipotent type B astrocytes type C precursors (TA cells) type A neuroblasts (migratory) interneurons 10
11 Seminiferous Tubules spermatogenesis Regulation of Stem Cells Should I stay quiescent? Should I die? Should I proliferate? Should I self-renew? Should I generate transit amplifying cells? Should I generate differentiating daughter cells? 11
12 Regulation of Stem Cells Signalling pathways Transcriptional response Cellular response Regulation of Stem Cells Jagged/ Dll γ-secretase Hes/Hey 12
13 Regulation of Stem Cells The Hippo Pathway Wnt pathway in epidermal stem cell regulation WNT β-catenin mouse mutant 13
14 Hh pathway in epidermal stem cell regulation Notch pathway in epidermal stem cell regulation promotes basal cells to become spinous cells Jagged/ Dll γ-secretase Notch expression Basal epidermal cells Hes/Hey 14
15 Hippo pathway in epidermal stem cell regulation Transgenic mouse expressing hyperactive YAP in basal cells Wildtype mouse YAP transgenic mouse Increased proliferation in basal epidermal stem cells of YAP transgenic mice Proliferating cell nuclei Stem cell marker/nuclei YAP transgenic YAP2-5SA-ΔC skin Wildtype skin 15
16 Hyperproliferative hair follicle bulge stem cells in YAP transgenic epidermis Stem cells/ nuclei YAP transgenic skin Wildtype skin Conclusion YAP functions as a molecular switch to control epidermal stem cell proliferation. 16
17 What happens if cell renewal regulation goes wrong? Tumor Development 17
18 Genetic alterations in Cancer Mutations in genes that regulate cell proliferation and differentiation Oncogenes: promote cell division (Ras) Tumor suppressor genes: inhibit cell division and survival (p53) Mutations in Wnt pathway result in Adenomatous Polyposis Coli X hyperproliferation 18
19 Mutations in Hedgehog pathway result in Basal Cell Carcinoma X hyperproliferation Mutations in Notch pathway result in T cell acute lymphoblastic leukemia X hyperproliferation 19
20 Mutations in Hippo pathway result in skin cancer X X hyperproliferation YAP, Wnt and human skin cancer YAP β-catenin BCC SCC Melanoma Eeles, Key, Lambie, Soyer, Beverdam, unpublished work 20
21 ANAT3231: lectures overview Stem Cell Biology Tissue homeostasis and regeneration Stem cell biology Stem cell niches Stem cell regulation Stem cells and cancer Dr Annemiek Beverdam School of Medical Sciences, UNSW Wallace Wurth Building Room 234 ANAT3231: lab next week Journal club presentation Form groups of 3 or 4 students Let me know the groups at beginning of next lecture Dr Annemiek Beverdam School of Medical Sciences, UNSW Wallace Wurth Building Room 234 A.Beverdam@unsw.edu.au 21
ANAT3231: lectures overview
ANAT3231: lectures overview Stem Cell Biology Stem Cell Technology Resources: http://php.med.unsw.edu.au/cell biology/ Essential Cell Biology 3 rd edition Alberts Dr Annemiek Beverdam School of Medical
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