Lecture 5: The Stem Cell Niche
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Questions and Answers

What is the primary function of Wnt signaling in the intestinal crypts?

  • To regulate cell proliferation of intestinal stem cells (correct)
  • To initiate apoptosis in cells
  • To support nutrient absorption
  • To differentiate cells into secretory types

What occurs when Notch signaling is active within the intestinal crypts?

  • Cells differentiate into absorptive enterocytes (correct)
  • Cells proliferate rapidly without differentiation
  • Cells are more likely to become secretory cells
  • Cells are retained as stem cells and do not differentiate

How does the activity of Wnt signaling differ between the crypts and villi of the intestine?

  • Wnt signaling is active in the crypts where it supports proliferative growth (correct)
  • Wnt signaling is active in both regions to promote growth
  • Wnt signaling is active in the villi but inactive in crypts
  • Wnt signaling is inactive in the villi where cell turnover is high

What type of cells do inactive Notch signaling most likely lead to the formation of?

<p>Secretory cells like goblet and enteroendocrine cells (C)</p> Signup and view all the answers

Which of the following best describes the source of Epidermal Growth Factor (Egf)?

<p>Produced by various cells, including Paneth cells and enterocytes (B)</p> Signup and view all the answers

What role does the basement membrane play in the stem cell niche?

<p>It separates epidermis from dermis, offering a barrier. (D)</p> Signup and view all the answers

Which growth factor is primarily responsible for maintaining the undifferentiated state of epidermal stem cells?

<p>Wnt (B)</p> Signup and view all the answers

What is the primary function of the stem cell niche in skin regeneration?

<p>To provide a site for stem cell proliferation and maintenance. (C)</p> Signup and view all the answers

What is one way to experimentally assess the properties of stem cell niches?

<p>By depleting the niche of existing stem cells and adding new ones. (D)</p> Signup and view all the answers

Which of the following is true about bone marrow irradiation in the context of stem cell research?

<p>It provides evidence of the functionality of the bone marrow niche. (B)</p> Signup and view all the answers

How do epidermal stem cells behave as they move upward through the epidermal layers?

<p>They become more specialized before shedding from the surface. (A)</p> Signup and view all the answers

What is the significance of EGF in the context of the stem cell niche?

<p>It promotes cell proliferation and survival, aiding skin regeneration. (D)</p> Signup and view all the answers

Which component is NOT considered part of the stem cell niche?

<p>Genetic material (A)</p> Signup and view all the answers

What role does crosstalk play in the tumor microenvironment?

<p>It supports the survival and proliferation of cancer cells. (B)</p> Signup and view all the answers

What therapeutic implication arises from understanding the tumor microenvironment?

<p>Disrupting supportive signals within the niche could weaken the tumor. (D)</p> Signup and view all the answers

Which of the following does NOT influence stem cell behavior?

<p>Age of individual (A)</p> Signup and view all the answers

How does the tumor microenvironment facilitate metastasis?

<p>By supporting the spread of cancer through intrinsic properties. (B)</p> Signup and view all the answers

Which factor is NOT contributing to a healthy stem cell niche?

<p>Physical disturbances (C)</p> Signup and view all the answers

What is a major pathological example involving stem cell niches?

<p>Tumor microenvironment (A)</p> Signup and view all the answers

Which of the following is essential for maintaining stem cell behavior?

<p>Interaction with immune cells (D)</p> Signup and view all the answers

What does the term 'niche signals' refer to in the context of stem cell behavior?

<p>External factors influencing stem cell activity. (D)</p> Signup and view all the answers

Which type of cell is primarily responsible for secreting mucus in the intestinal lining?

<p>Goblet cells (D)</p> Signup and view all the answers

What is the primary function of Paneth cells in the intestinal stem cell niche?

<p>To provide niche support (C)</p> Signup and view all the answers

Which cells are located at the base of intestinal crypts and are responsible for the renewal of the intestinal epithelium?

<p>Intestinal stem cells (C)</p> Signup and view all the answers

Which signaling molecule is crucial for intestinal stem cell self-renewal and proliferation?

<p>Wnt (B)</p> Signup and view all the answers

What role do enteroendocrine cells play in the intestinal epithelium?

<p>Hormone production (D)</p> Signup and view all the answers

Which of the following is NOT a function of the signaling pathways in the intestinal stem cell niche?

<p>Inhibiting the proliferation of stem cells (B)</p> Signup and view all the answers

From where do intestinal stem cells derive all other cell types within the intestinal lining?

<p>ISCs themselves (A)</p> Signup and view all the answers

What is the primary source of the Wnt signaling molecule in the intestinal niche?

<p>Mesenchymal cells (C)</p> Signup and view all the answers

The interaction between intestinal stem cells and Paneth cells is critical for what signaling pathway?

<p>Notch pathway (D)</p> Signup and view all the answers

What type of cells can be found scattered throughout the intestinal epithelium and are known for their hormone production?

<p>Enteroendocrine cells (A)</p> Signup and view all the answers

What effect does disrupting the Wnt signaling pathway have on spermatogonial stem cells as observed in the experimental setup?

<p>It causes a significant gap in the tubules. (B)</p> Signup and view all the answers

Which statement accurately describes the location and function of intestinal stem cells?

<p>They reside near the base of crypts and are essential for epithelial cell renewal. (D)</p> Signup and view all the answers

What is the primary function of absorptive enterocytes in the intestinal epithelium?

<p>Absorption of nutrients and maintenance of intestinal barrier. (B)</p> Signup and view all the answers

What differentiates the colonic epithelium from the small intestinal epithelium?

<p>Colonic epithelium lacks villi. (D)</p> Signup and view all the answers

Which types of cells primarily remain around the edges of the tubules in the mutant mouse after Wnt signaling disruption?

<p>Sertoli cells. (B)</p> Signup and view all the answers

What are the differentiated cell types found in the intestinal epithelium?

<p>Enterocytes, Goblet cells, Paneth cells, and enteroendocrine cells. (D)</p> Signup and view all the answers

How does the arrangement of cells in the small intestinal epithelium contribute to its function?

<p>Cells are organized into crypts and villi to maximize surface area for absorption. (D)</p> Signup and view all the answers

What role do Paneth cells play in the intestinal niche?

<p>They secrete antimicrobial molecules. (C)</p> Signup and view all the answers

What is indicated by the presence of differentiating sperm cells visible as little lines in the center of the tubules in wild type mice?

<p>Normal spermatogenesis. (B)</p> Signup and view all the answers

What type of cells are primarily responsible for maintaining the testis environment and supporting germ cells?

<p>Sertoli cells. (A)</p> Signup and view all the answers

Flashcards

What is the Basement Membrane?

A specialized structure separating the epidermis and dermis, acting as a physical and biochemical barrier.

What is a Differentiation Gradient?

Stem cells differentiate as they move upward through the epidermis, becoming more specialized before shedding from the skin's surface.

What is Wnt?

A critical signaling molecule that maintains the undifferentiated state of epidermal stem cells.

What is EGF?

A growth factor that promotes cell proliferation and survival, playing a key role in skin regeneration and repair.

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What is the function of a stem cell niche?

This niche is crucial for the continuous renewal of the skin and for repair processes such as wound healing or regeneration.

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Describe an assay to determine stem cell properties.

An assay that involves depleting the niche of existing stem cells and then introducing a candidate cell population into the niche.

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Give an example of a stem cell niche perturbation approach.

Irradiating bone marrow to deplete hematopoietic stem cells and then transplanting donor stem cells. It confirms both the identity of the stem cells and the functionality of the bone marrow niche.

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Stem Cell Niche

The surroundings that influence stem cell behavior, including survival, differentiation, and potential tumor formation.

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Tumor Microenvironment

The surrounding tissue environment that supports and sustains cancer cells.

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Crosstalk in Tumor Microenvironment

The interaction between cancer cells and the surrounding cells in the microenvironment, which drives tumor growth and metastasis.

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Extracellular Matrix

A component of the stem cell niche that provides physical support and organization to stem cells.

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Secreted Factors

A component of the stem cell niche that can influence stem cell differentiation by activating or inhibiting specific genes.

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Hypoxia

An environment with low oxygen levels, which can influence stem cell behavior.

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Drosophila Testis

A key feature of the Drosophila testis that allows for easy identification of key niche signals.

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Niche-Targeting Therapy

A therapy that focuses on disrupting the supportive signals within the niche to weaken the tumor or prevent it from spreading.

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Cancer Stem Cells

A type of stem cell found in tumors that contributes to cancer growth and metastasis.

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Wnt Signaling Pathway

A signaling pathway that plays a crucial role in regulating stem cell self-renewal and differentiation.

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Sertoli Cells

Specialized cells in the testes responsible for supporting and nurturing developing sperm cells.

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Stem Cells

Undifferentiated cells that have the potential to self-renew and differentiate into various cell types.

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Stem Cell Maintenance

The process of stem cell self-renewal and differentiation into specialized cell types.

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Spermatogonial Stem Cells

A type of stem cell found in the testes, responsible for the production of sperm cells.

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Villi

Finger-like projections in the small intestine that increase the surface area for nutrient absorption.

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Crypts

Depressions in the intestinal wall that contain stem cells and their progeny.

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Enterocytes

Specialized cells in the intestinal epithelium that absorb nutrients and maintain the gut barrier.

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Goblet Cells

Specialized cells in the intestinal epithelium that secrete mucus to lubricate and protect the lining.

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What is the Wnt signaling pathway?

A signaling pathway crucial for regulating cell proliferation in the intestine. It is highly active in the intestinal crypts, driving the growth of intestinal stem cells. This ensures a steady supply of new cells to replace those lost during normal turnover.

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What is the Notch signaling pathway?

A signaling pathway that controls cell fate within the intestinal epithelium, determining whether cells become absorptive or secretory. Active Notch signaling promotes differentiation into absorptive enterocytes, while inactive Notch encourages differentiation into secretory cells.

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What are absorptive enterocytes?

Cells responsible for nutrient absorption in the villi. They are created when Notch signaling is active in intestinal crypts.

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What are secretory cells?

Cells that produce mucus (goblet cells) or hormones (enteroendocrine cells). They are formed when Notch signaling is inactive in intestinal crypts.

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What is EGF (Epidermal Growth Factor)?

A growth factor produced by cells like Paneth cells and enterocytes. It stimulates cell proliferation and survival in the intestinal epithelium.

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Paneth Cells

Specialized cells found at the base of intestinal crypts, supporting intestinal stem cells by secreting antimicrobial peptides and growth factors.

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Enteroendocrine Cells

Cells within the intestinal lining responsible for producing hormones that regulate digestion and gut motility.

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Intestinal Crypt Stem Cell Niche

A specialized microenvironment in the intestinal crypt that provides essential support and signals for the maintenance and renewal of intestinal stem cells.

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Transient Amplifying Cells

A type of cell produced by intestinal stem cells that serves as a transient intermediary, gradually maturing and differentiating to become various cell types.

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Wnt Signaling

A signaling pathway crucial for intestinal stem cell self-renewal and proliferation, activated by Wnt ligands secreted from Paneth cells and mesenchymal cells.

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Notch Signaling

A signaling pathway regulated by interactions between intestinal stem cells and neighboring cells, including Paneth cells, that controls cell fate decisions and differentiation. It helps maintain a balance between stem cell renewal and the production of specialized cell types.

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Telocytes

A type of cell found in the supporting niche of intestinal stem cells, involved in maintaining the stem cell pool and influencing cell fate decisions.

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Stromal Cells

Cells found within the supporting niche of intestinal stem cells, contributing to the microenvironment and influencing stem cell behavior.

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Macrophages

Immune cells found in the stem cell niche, playing a role in regulating stem cell behavior and protecting against infection.

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EGF (Epidermal Growth Factor)

A signaling molecule that plays a crucial role in intestinal stem cell proliferation and survival, promoting the growth and expansion of the stem cell population.

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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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