Stem cells

Question 1

Embryonic stem cells

Answer 1

• Totipotent stem cells: cells formed soon after fertilization, can form all cell types of embyro + placenta + extraembyronic tissues
• Pluripotent stem cells: can form all cell types of the embyro
• Embryonic stem cells: derived from inner cell mass of blastocyst
• Induced pluripotent stem cells (iPSC): four transcription factor genes (c-Myc, Oct3/4, Sox2, Klf4) can transform adult somatic cells into pluripotent stem cells

Question 2

Adult stem cells

Answer 2

• Undifferentiated
• Divide indefinitely
• Self-renew
• Reside in a stem cell niche
• Mother cell of a cell lineage

Question 3

Three kind of cell populations

Answer 3

• “Static cell populations”: no adult stem cells, only non-dividing mature cells. eg. neurons
• “Expanding cell populations”: small number of adult stem cells that divide as needed then differentiate into the mature cell type (skeletal muscle, liver, pancreas)
• “Renewing cell populations”: numerous adult stem cells operating via progenitor scheme to produce mature cells for normal function. hematopoietic system, intestinal epithelium, and epidermis are fastest renewing cell populations in the body, with daily cellular turnover (average number of newly produced/dead cells per day) of 10^9, 10^8, 10^7 in hematopoietic, intestinal, and epidermis respectively

Question 4

Two mechanisms of stem cell division

Answer 4

• Asymmetric cell division: divide into one stem cell and one progenitor
• Stochastic differentiation: Randomly determined (Two stem cells, two progenitors, one of each)

Question 5

Stem cell niche

Answer 5

• Microenvironment in tissue where stem cells reside
• Niche factors maintaining nature of stem cells may include: soluble factors, extracellular matrix components, cell associated molecules
• Epithelial stem cells depend on three different factors: Wnt/R-spondin factors, Ligand of tyrosine kinase receptors, Inhibitors of TGFb/BMP superfamily (gremlims, noggins)

Question 6

Process

Answer 6

Adult stem cells (undifferentiated) -> Progenitors -> Multipotent progenitor (cannot divide indefinitely, differentiate into more than one cell type) or Unipotent precursor (cannot divide indefinitely, differentiate into only one cell type)

Question 7

Stem Cell Discovery

Answer 7

• Till and McCulloch discovered hematopoietic stem cell in mice
• Till, McCulloch, Becker, and Siminovich confirmed that each clone was derived from a single cell
• Siminovich et al showed that colony forming cells are capable of self renewal
• Hematopoietic stem cells exist in bone marrow

Question 8

Stem Cell Diseases

Answer 8

• Neurodegenerative diseases
• Cardiovascular diseases
• Cancer
• Aging
• Diabetes

Question 9

Stem Cell Therapy

Answer 9

• Hematopoietic stem cell transplantation for leukemia and lymphoma: bone marrow transplantation, umbilical cord blood
• Skin: autologous healthy epidermal stem cells can be cultured to treat burns, stem cell culture rescues a laminin mutation genetic diseases causing skin blistering
• Cornea: limbal stem cells in cornea expanded to cure blindness
• Clinical trials: organoids derived from salivary gland stem cells to treat cancer patients, intestinal organoids to treat ulcerative colitis, iPSC derived cardiomyocytes to treat heart failure

Question 10

Cancer Stem Cells

Answer 10

• Small group of cells in tumors that express stem cell properties (self-renewal, proliferation, pluripotency, and can lead to tumorigenesis and metastasis)
• Proportion (0.2 - 82%) varies among primary tumor types
• Negative correlation between presence of CSCs and patient survival in various cancers

Question 11

Origins of Cancer Stem Cells

Answer 11

• Differentiated cells
• Stem or progenitor cells
• Cell-cell fusion of various cell types
• Ionizing radiation induction

Question 12

Cancer Stem Cell Niche

Answer 12

• Hypoxia
• Aberrant angiogenesis
• Chronic inflammation
• Cancer associated fibroblasts: hyperproliferative interstitial cells, contributes to tumor angiogenesis and metastases
• Mesenchymal stem cells: recruited during tumor initiation and development, followed by constant recruitment to microenvironment
• Tumor associated macrophages: M1 pro inflammatory and M2 anti-inflammatory
• Myeloid derived suppresor cells: heterogeneous group of cells of myeloid lineage that are immunosuppressive

Question 13

CSCs marker

Answer 13

• Intracellular
• Cell surface
• Cytoplasmic proteins

Question 14

Formation and maintenance of CSCs involve complex interactions between multiple signaling pathways

Answer 14

• WNT/B-catenin
• Hedgehog
• Notch pathway
• NF-B
• JAK/STAT
• TGF-B
• P13K/AKT
• PPAR

Question 15

Cancer metastasis

Answer 15

• Involve several processes: cell escape, intravasation, survival maintenance, extravasation, out growth

Question 16

Mechanism of resistance of CSCs to chemotherapy

Answer 16

• CSCs exhibit dynamic states of proliferation and quiescence
• Survive for prolong period during dormancy
• Resume proliferation upon extracellular stimulation
• Chemotherapy targets rapidly dividing cells in a cell cycle specific manner
• Resistant to chemotherapy and develop more resistant phenotypes