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Questions and Answers
What is the primary function of Wnt signaling in the intestinal crypts?
What is the primary function of Wnt signaling in the intestinal crypts?
What occurs when Notch signaling is active within the intestinal crypts?
What occurs when Notch signaling is active within the intestinal crypts?
How does the activity of Wnt signaling differ between the crypts and villi of the intestine?
How does the activity of Wnt signaling differ between the crypts and villi of the intestine?
What type of cells do inactive Notch signaling most likely lead to the formation of?
What type of cells do inactive Notch signaling most likely lead to the formation of?
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Which of the following best describes the source of Epidermal Growth Factor (Egf)?
Which of the following best describes the source of Epidermal Growth Factor (Egf)?
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What role does the basement membrane play in the stem cell niche?
What role does the basement membrane play in the stem cell niche?
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Which growth factor is primarily responsible for maintaining the undifferentiated state of epidermal stem cells?
Which growth factor is primarily responsible for maintaining the undifferentiated state of epidermal stem cells?
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What is the primary function of the stem cell niche in skin regeneration?
What is the primary function of the stem cell niche in skin regeneration?
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What is one way to experimentally assess the properties of stem cell niches?
What is one way to experimentally assess the properties of stem cell niches?
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Which of the following is true about bone marrow irradiation in the context of stem cell research?
Which of the following is true about bone marrow irradiation in the context of stem cell research?
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How do epidermal stem cells behave as they move upward through the epidermal layers?
How do epidermal stem cells behave as they move upward through the epidermal layers?
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What is the significance of EGF in the context of the stem cell niche?
What is the significance of EGF in the context of the stem cell niche?
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Which component is NOT considered part of the stem cell niche?
Which component is NOT considered part of the stem cell niche?
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What role does crosstalk play in the tumor microenvironment?
What role does crosstalk play in the tumor microenvironment?
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What therapeutic implication arises from understanding the tumor microenvironment?
What therapeutic implication arises from understanding the tumor microenvironment?
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Which of the following does NOT influence stem cell behavior?
Which of the following does NOT influence stem cell behavior?
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How does the tumor microenvironment facilitate metastasis?
How does the tumor microenvironment facilitate metastasis?
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Which factor is NOT contributing to a healthy stem cell niche?
Which factor is NOT contributing to a healthy stem cell niche?
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What is a major pathological example involving stem cell niches?
What is a major pathological example involving stem cell niches?
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Which of the following is essential for maintaining stem cell behavior?
Which of the following is essential for maintaining stem cell behavior?
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What does the term 'niche signals' refer to in the context of stem cell behavior?
What does the term 'niche signals' refer to in the context of stem cell behavior?
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Which type of cell is primarily responsible for secreting mucus in the intestinal lining?
Which type of cell is primarily responsible for secreting mucus in the intestinal lining?
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What is the primary function of Paneth cells in the intestinal stem cell niche?
What is the primary function of Paneth cells in the intestinal stem cell niche?
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Which cells are located at the base of intestinal crypts and are responsible for the renewal of the intestinal epithelium?
Which cells are located at the base of intestinal crypts and are responsible for the renewal of the intestinal epithelium?
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Which signaling molecule is crucial for intestinal stem cell self-renewal and proliferation?
Which signaling molecule is crucial for intestinal stem cell self-renewal and proliferation?
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What role do enteroendocrine cells play in the intestinal epithelium?
What role do enteroendocrine cells play in the intestinal epithelium?
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Which of the following is NOT a function of the signaling pathways in the intestinal stem cell niche?
Which of the following is NOT a function of the signaling pathways in the intestinal stem cell niche?
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From where do intestinal stem cells derive all other cell types within the intestinal lining?
From where do intestinal stem cells derive all other cell types within the intestinal lining?
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What is the primary source of the Wnt signaling molecule in the intestinal niche?
What is the primary source of the Wnt signaling molecule in the intestinal niche?
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The interaction between intestinal stem cells and Paneth cells is critical for what signaling pathway?
The interaction between intestinal stem cells and Paneth cells is critical for what signaling pathway?
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What type of cells can be found scattered throughout the intestinal epithelium and are known for their hormone production?
What type of cells can be found scattered throughout the intestinal epithelium and are known for their hormone production?
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What effect does disrupting the Wnt signaling pathway have on spermatogonial stem cells as observed in the experimental setup?
What effect does disrupting the Wnt signaling pathway have on spermatogonial stem cells as observed in the experimental setup?
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Which statement accurately describes the location and function of intestinal stem cells?
Which statement accurately describes the location and function of intestinal stem cells?
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What is the primary function of absorptive enterocytes in the intestinal epithelium?
What is the primary function of absorptive enterocytes in the intestinal epithelium?
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What differentiates the colonic epithelium from the small intestinal epithelium?
What differentiates the colonic epithelium from the small intestinal epithelium?
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Which types of cells primarily remain around the edges of the tubules in the mutant mouse after Wnt signaling disruption?
Which types of cells primarily remain around the edges of the tubules in the mutant mouse after Wnt signaling disruption?
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What are the differentiated cell types found in the intestinal epithelium?
What are the differentiated cell types found in the intestinal epithelium?
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How does the arrangement of cells in the small intestinal epithelium contribute to its function?
How does the arrangement of cells in the small intestinal epithelium contribute to its function?
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What role do Paneth cells play in the intestinal niche?
What role do Paneth cells play in the intestinal niche?
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What is indicated by the presence of differentiating sperm cells visible as little lines in the center of the tubules in wild type mice?
What is indicated by the presence of differentiating sperm cells visible as little lines in the center of the tubules in wild type mice?
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What type of cells are primarily responsible for maintaining the testis environment and supporting germ cells?
What type of cells are primarily responsible for maintaining the testis environment and supporting germ cells?
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Study Notes
The Stem Cell Niche
- Stem cell niches are microenvironments where stem cells reside and receive signals to determine their fate.
- These niches have a significant effect on how stem cells behave and are essential for understanding how stem cells grow and how they can be transplanted.
- Niches can determine whether a stem cell produces normal tissue or a tumour.
- Embryonic stem cell differentiation is greatly influenced by the surrounding environment.
- Injecting embryonic mouse stem cells into a blastocyst leads to normal development.
- Injecting the same cells under the skin of a mouse leads to abnormal tumour formation (teratocarcinoma).
- Environmental context greatly influences cell function, as seen in blastocyst vs. skin injection examples.
- The environment's importance in determining cell behaviour is highlighted by these contrasting outcomes.
Model Systems for Studying Niches
- Drosophila germline: Used to study niche signals and stem cell behaviour.
- Drosophila testis are large relative to the fly's body: This makes studying germline stem cells, which reside at the tip, easier.
- Drosophila sperm tails stretch along the length of the testis: This morphology is important for studying the process of differentiation.
- Germline stem cells reside at the tip of the testis: This specific location is crucial for understanding their behaviour.
- Drosophila are non-essential to fly viability: This characteristic is advantageous because genetic studies and manipulations can be performed safely without impacting fly survival.
Key Components in Mammalian Niches
- Hematopoietic Stem Cells (HSCs): These stem cells generate all blood cell types.
- Endothelial cells: Line blood vessels and provide signals/structural framework supporting HSCs.
- Mesenchymal Stem Cells (MSCs): Support HSC maintenance/differentiation through secretion of specific factors.
- Neurons: Play a role by providing signals and shaping HSCs.
- Extracellular Matrix (ECM): Provides a scaffold for cells in the niche, influencing cell behaviour. ECM components like fibronectin influence behaviour of the stem cells mechanically and biochemically.
Skin Stem Cell Niche
- Location: Basal layer of the skin's epithelium, near the basement membrane.
- Key Components: Epidermal stem cells (responsible for the continuous renewal of the skin).
Niche Hypothesis (Schofield)
- Stem cells reside in fixed compartments.
- Niches support the maintenance of stem cell properties.
- Niches provide signals (secreted, surface molecules) that control stem cell proliferation and fate.
Niche Components and Cancer
- Niche components in the tumor microenvironment drive cancer development.
- Crosstalk between cancer cells and surrounding cells (microenvironment) drives growth and spread (metastasis).
- Microenvironment and intrinsic properties of cancer cells determine the spread of the disease.
- Cancer cells are sustained by the tumor environment. Cancer stem cells are key to this process. Targeting the niche may be more effective than directly targeting the tumor.
Intestinal Stem Cell Niche
- Intestinal epithelium is composed of crypts and villi.
- Stem cells reside near the base of crypts – they continuously renew the entire epithelial cell layer.
- Specialized cells (enterocytes, goblet cells, paneth cells, and enteroendocrine cells) are derived from from stem cells.
Key Cell Types and Signals in the Intestinal Stem Cell Niche
- Intestinal stem cells: Located at base of crypts.
- Paneth cells: Located at the base of crypts; secrete antimicrobials, growth factors.
- Stromal cells: Support stem cells.
- Transit-amplifying cells: Differentiate into mature cells and migrate up the crypts.
- Macrophages: Involved in the niche.
- Telocytes: Involved in the niche.
- Key Signals: Wnt, R-spondin, Noggin, BMP, EGF, NRG1 are critical for niche function, signaling and regulating proliferation/differentiation.
Wnt and Notch Signalling in the Intestine
- Wnt Signaling Pathway: Crucial for regulating cell proliferation within the intestine.
- Wnt is active in crypts: Drives ISC proliferation.
- Wnt is inactive in villi: Minimal proliferation.
- Notch Signaling Pathway: Determines cell fate, influencing whether cells become absorptive or secretory.
- Notch active in crypts: Increases differentiation to absorptive enterocytes.
Assays to Identify Intestinal Stem Cells
- Genetic Strategy (eg, linear tracing): Gentically marking stem cells.
- Introduced marker: Allows visualization of stem cells and progeny.
- Isolation and culture: Culturing to create organoid cultures.
Organoid Cultures and Transplantation Assays
- Cultured Lgr5+ stem cells differentiate into all cell types of the intestinal epithelium, in organoids.
- These organoids are used to assess the transplantation of cells into damaged tissue, with potential therapeutic implications.
Lineage Tracing
- Lineage tracing experiments have determined that LGR5 cells generate various types of cells in the intestinal tissue.
Key Components for Lineage tracing
- LGR5 gene locus with GFP.
- GFP: Attached to LGR5 promoter that labels LGR5 positive cells with green fluorescence allowing visualization in a microscope.
- CRE Recombinase Gene, CRE-ER2 (modified version).
- Reporter construct with LacZ: Cells are blue when substrate is added.
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