L13- Stem cell niche

Question 1

What is a niche?

Answer 1

All of the physical, chemical and biological factors a species needs to survive, stay healthy and reproduce in an ecosystem

Question 2

What is the stem cell niche?

Answer 2

A specialised microenvironment housing stem cells, ability of stem cells to self-renew and retain their identity depends on the environment provided by neighbouring (non-stem) cells.

Question 3

How is stem cell fate regulated?

Answer 3

1. Intrinsic state of the cell e.g key transcription factors
2. Stimuli from the microenvironment
3. Remodelling of the niche by stem cells (by secreted factors)

Question 4

How do cell components influence stem cell fate?

Answer 4

Heterologous cell-cell interactions are present and exhibit bi-directional signalling that is dependent on tight regulation and cell-cell contact

Question 5

How do secreted factors influence stem cell fate?

Answer 5

Secreted and membrane bound factors directly bind surface receptors on stem cells to regulate cell fate, self renewal and polarity

Question 6

How do immune cells influence stem cell fate?

Answer 6

Immune cells provide dynamic regulation of the niche during inflammation and tissue damage

Question 7

How does the extracellular matrix influence stem cell fate?

Answer 7

ECM contains proteins which are critical for the orientation and structural maintenance of the niche

Question 8

How do physical factors influence stem cell fate?

Answer 8

Physical parameters such as shape, stiffness or elasticity and blood flow direct stem cell maintenance and differentiation

Question 9

How do environmental characteristics influence stem cell fate?

Answer 9

Some stem cell niches have hypoxia and require tight metabolic regulation to maintain the long term quiesence and self renewal of the stem cell populations

Question 10

What are the factors in the HSC niche?

Answer 10

• Physical factors= substrate elasticity
• Secreted factors= chemokines, Wnt
• ECM
• Hypoxic environment

Question 11

What are the factors in the intestinal stem cell niche?

Answer 11

• Secreted factors= Wnt, DLL, EGF
• Basement membrane- structure, polarity
• Physical factors= elasticity
Differentiation occurs from bottom to top

Question 12

What are the factors in the epidermal stem cell niche?

Answer 12

• Secreted factors= Wnt, DLL, EGF
• Cell-cell contact - differentiation (signal transfer)
• ECM- polarity
• Physical factors- elasticity, topography

Question 13

How is the stem cell niche manipulated in vitro and in vivo?

Answer 13

• Patterning ligands on substrates
• Controlling rheological properties of cellular environment
• Presenting cells with different topographical features

Question 14

How does niche dysfunction occur in epithelial cancer progression?

Answer 14

1. Injury induced regeneration or during normal homeostasis stromal niche provides differentiative and proliferative signals to the overlying epithelium
2. Early stages of cancer- genetic lesions form with intrinsic proliferative effects in growing tumour cells means stem cell niche signals not needed
   - stem cell niche can still restrain tumour growth here
3. Modification of niche by tumour cells prevents production of differentiation-inducing factors allowing unrestrained cancer cell growth

Question 15

How are cancer cells formed?

Answer 15

• Normal progenitor cell escapes regulation and becomes a cancer progenitor cell
• Gives rise to poorly differentiated cells/ subtypes of tumours
• Cancer progenitor cells can de-differentiate to become CSC’s due to plasticity
• Can form normal or cancerous progenitor cells

Question 16

How do cancer stem cells take over the niche?

Answer 16

• Hijack normal niche
• Upregulate epithelial-mesenchyme transformation pathways in the surrounding normal cells to transform them into CSC’s
• Primary CSC’s can manipulate distant tissue niches to create a metastatic niche for their future arrival
• By releasing growth factors that induce chemotactic protein expression and ECM remodelling

Question 17

Where are stem cell niches used as therapeutic targets?

Answer 17

• Blood- transfusion after chemotherapy
• Skin- grafts, scaffolds
• Muscle- satellite cells
• Bone- bone- tissue scaffolds
 (revise from notes)