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Molecular Biology > Mechanism Kf Stem Cell Renewal And Cancer > Flashcards

Mechanism Kf Stem Cell Renewal And Cancer Flashcards

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1
Q

What are stem cells?

A

Unspecialized cells that have the potential to self- renew(by division) and develop into more mature, specialized cells.

It has unique capacity to produce unaltered daughter cells (self-renewal) and to generate specialized cell types (potency)
-When a stem cell divides, each new cell may remain a stem cell or become another cell type with a more specialized function, such as a muscle cell, a red blood cell or brain cell

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2
Q

What are the characteristics of stem cells?

A

They can d8vide and renew themselves for long periods

  • they are unspecialized, therefore, they cannot perform specific functions in the b9dy
  • they have the capacity to become specialized cells, such as muscles cells, blood cells, and brain cells
  • Stem cells can replace damaged, dying or old cells
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3
Q

What are the potential uses of stem cells?

A

-For increase understanding of disease pathogenesis so as to suggest new strategies for therapy

-To generate healthy cells to replace diseased cells (regenerative cells):
E.g. spinal cord injury, stroke,burns, heart disease, diabetes, osteoarthritis, and rheumatoid arthritis

Human stem cells are presently being used to test new drugs for safety, effectiveness and efficiency: Drug development

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4
Q

What are the strategies of transplantation of stem cells?

A
  1. Undifferentiated or partially differentiated stem cells may be injected directly into the target organ or introduced intravaneiusly
  2. Stem cells may be differentiated ex vivo before being injected into the target organ
  3. Growth factors or other drugs may be injected to stimulate endogenous stem cells
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5
Q

What is totipotent?

A

Stem cells able to generate every cell type including extraembryonic (placental) tissues. Totipotent stem cells can form an entire organism autonomously. Only a fertilized egg (zygote) possesses this capability

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6
Q

What is pluripotent?

A

Stem cells able to generate cells from all three embryonic germ layers. Pluripotent cells (e.g., embryonic stem [ES]) can form almost all of the body’s cell lineages (endoderm, mesoderm, and ectoderm), including germ cells, except the placenta

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7
Q

What is multi potent?

A

Stem cells are able to generate a variety of cells from a particular somatic structure. Multi potent cells(e.g., hematopoietic stem. [HS]) can form multiple cell lineages but cannot form all of the body’s cell lineages

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8
Q

What is unipotent?

A

Stem cells only generate one cell type. Unipotent cells or mono potent cells (e.g., spermatogonia cells[SS]) can form a singed differentiated cell lineage

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9
Q

What are the levels 0f potentcy

A

Totipotent—> pluripotent—> multipotent—> unipotent

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10
Q

What are the types of stem cells?

A

Embryonic stem cells

Somatic or adult stem cells

iPSCs- induced pluripotent stem cells

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11
Q

Explain embryonic stem cells

A

Derived from the inner cell mass of the blastocyst (preimplantation embryos) , before formation of the 3 germ layers (ectoderm, endoderm, mesoderm)

Embryonic stem cells are pluripotent:
-they can give rise to every cell type in the fully formed body, but not the placenta and umbilical cord

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12
Q

Explain adult or somatic stem cells

A
  • Undifferentiated stem cells found in specific locations in “mature” tissues
  • These tissue-specific stem cells are more specialized than embryonic stem cells

Typically they can generate different cell types for the specific tissue or organ in which they are located

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13
Q

Explain induced pluripotent stem cells

A

Engineered in the lab by converting tissue specific cells (e.g., skin cells) into cells that behave like embryonic stem cells

iPS cells help scientists learn more about normal development and disease onset andprpfression,

They are also valuable for developing and testing new drugs and therapies

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14
Q

What is stem cell renewal?

A

The process by which stem cells divide to make more stem cell pool through life

Self renewal entails division with maintenance of th3 undifferentiated state

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15
Q

Describe stem cell self renewal by asymmetric cell divisional

A

Asymmetric cell division produces one daughter cell that is identical to the the parental cell and one daughter cell that is different from the parental cell and is a progenitor or differentiated cell

Asymmetric cell divisoon doesn’t increase the number of stem cell

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16
Q

Describe symmetric cell division.

A

Symmetric cell division produces two identical daughter cells

-for stem cells to proliferate in vitro, they must divide summetrically

17
Q

What is the importance of self-renewal ?

A

The ability to self-renew is essential for stem cells to:

- Expand their numbers during development
- Be maintained within adult tissues
- Restore the stem cell pool after injury

Defects in self-renewal mechanisms may lead to:

- Developmental defects
- Premature aging phenotypes 
- Cancer

The understanding of self-renewal mechanisms offers fundamental insights into development, cancer, and aging

18
Q

What are the intrinsic mechanisms in cell division of normal stem cells?

A

During cell division, a subpopulation of proteins, RNAs, and other macromolecules in mother cells are inherited unequally into two daughter cells

  • Unequally distributed cellular components include fate determinants that govern the fates of two daughter cells.
  • During asymmetric cytokinesis, the apical daughter cell, which is larger in size, inherits self-renew-promoting factors and remains as the stem cell lineage. The smaller, basal cell inherits differentiation factors
  • During symmetrical division, spindle orientation and determinant protein (e.g., Numb) localization aren’t coordinated. Determinants segregate equally, giving rose to two equal (stem) cells
19
Q

Describe cell-extrinsic mechanisms of regulating stem cells

A

Cell-intrinsic mechanisms are regulated by cell-extrinsic signals from the niche, the micro environment that maintains stem cells and regulates their function in tissues.

Most stem cells in metazoans reside within specialized micro environments called niches

These niches contain cells which promotes stem cell maintenance and regulate system function

Niche cells are able to carry out these functions by providing an Anchorage site for stem cells as well as by producing membrane bound and secreted signals that regulate stem cell survival, cell cycle status, and differentiation

  • Often times, the size and availability of niches physically limits the number of stem cells in tissues
  • Didplacement of cells from the niche often makes these cells to differentiate as they lose access to niche signals that are required to remain undifferentiated
20
Q

What are the extrinsic mechanisms in cell division of normal stem cells ?

A
  • Asymmetric cell division is also influenced by the extracellular environment
  • During division, stem cells ensure that only one progeny can be in contact with the stem niche by keeping the perpendicular orientation of their mitotic spindle to the niche surface
  • The progeny in contact with the stem cell niche retains self-renewal ability, while the other undergoes differentiation
  • In comtrast to the intrinsic mechanism which usually follows a predefined program, the environmental niche-dependent extrinsic mechanism is quite flexible
  • It has been known that extrinsic mechanisms p,say critical role fir the choice of symmetric or asymmetric divisions in HSCs.
  • HSCs mainly divide asymmetrically when cultured on the layer of osteoblasts cells cells but undergo symmetric cell division on the layer of stromal cells, suggesting that HSCs control self renewal process through interaction with the environmental niche
21
Q

Self renewal programs involve networks which:

A

Balance proto-oncogenes (promoting self-renewal)

  • Gatd-keeping tumor suppressors (limiting self-renewal)
  • Care taking tumor suppressor (maintaining genomic integrity)
22
Q

Explain the response of stem cells to changing tissue demands over time and in different stages of life

A
  • In response to changing tissue demands, stem cells undergo in cell cycle status and developmental potential over time, requiring different self-renewal programs at different stages of life
  • Self-renewal programs depend on major transcriptional regulators that are often shared among stem cells in different tissues but which often change between stem cells at different stages of life
  • A key requirement for self-renewal is repression of the p15(InK4a) and p19(Arf) tumor suppressors. This is accomplished by overlapping transcriptional regulators whose expression and function change with age, so as to maintain self-renewal potential throughout life, at the same time allowing increased expression of p16(lnk4a) and p19(Arf) in aging stem cells. This reduces stem cell function in aging tissues but also reduces the incidence of cancer
23
Q

What is the mechanism of reduced stem cell function during aging?

A
  • Aging is associated with a reduction in regenerative capacity of organ stem cells, resulting to accumulation of unrepaired, damaged tissues in the old organism
  • Reduced stem cell function and tissue regenerative capacity during aging are a result of changes in self-renewal programs that augment tumor suppression
  • Several interactive signaling networks become altered in organ stem cells and in their differentiated niches during the aging process
24
Q

Summarize the mode of division and cell- cycle properties in normal and cancer stem cells

A

Normal SCs divide mainly assymetrically giving rise to stem cell (SC) and progenitor(P) cells. Their self-renewal potential is intrinsically restricted, therefore, they functionally exhaust once they reach the limit of six to seven divisions

  • In normal SCs, p53-dependent regulation of c-Myc imposes an asymmetric mode of division and p21 maintains self-renewal
  • In cancer stem cells(Csc), self-renewal capability is seriously deregulated. Critical to tumor expansion, loss of p53 results in a switch to the symmetric mode of cell division , and upregulation of p21 extends the self renewal ability of CSCs
  • The CSCs undergo an indefinite number of rounds of cell division, which, ultimately, results in the expansion of the stem cell pool
25
Q

Summarize the differences between extrinsic and intrinsic aging mechanisms in satellite cells and hematopoietic stem cells

A
  • The satellite cell pool and the HSC reserve pools don’t decline with age, but their functional properties do deteriorate with age.
  • unlike HSCs, muscle stem cells are intrinsically capable of life-long maintenance and repair of skeletal muscle, but the functional ability of these stem cells to proliferate in response to tissue injury or attrition is severely affected by the aging of their local niches, I.e., differentiated myofivers and ECM
  • The behavior of old muscle stem cells can be remarkably rejuvenated in “young” environments
26
Q

Summarize the Cancer Stem Cell(CSC) or Cancer Initiating Cancer (CIC) Model

A

Self renewal is one of the important properties employed by the CSCs to maintain the proliferating capacities

Human CSCs are defined by their ability to:
-(I) generate a xenograph that histologically resembles the parent tumor from which it was derived

  • (II) be serially transplanted in a xenograft assay thereby showing the ability to self-renew(regenerate)
  • (III) generate daughter cells that possess some proliferative capacity but are unable to initiate or maintain the cancer because they lack intrinsic regenerative potential
27
Q

What are the multiple facets to CSC self-renewal?

A
  • CSC self-renewal decisions can be guided by the activation of several pathways, including:
    • Wnt
    • Notch
    • Hedgehog
    • B-cell-specific moloney murine leukemia virus integration site 1 (BMI1) pathways, and others
  • A CSC may autonomously trigger the appropriate signaling cascade to maintain self-renewal with minimal niche support
  • it is possible that some CSCs need the appropriate micro environment to provide the stimuli fir uncontrolled self-renewal
  • Some cancer cells have lost the capacity to self-renew regardless of stimulating molecules, therefore cannot initiate a tumor
28
Q

Explain the Wnt pathway

A

The Wnt pathway signaling pathway is an ancient and evolutionary conserved developmental pathway that controls stem cells and cellular fate during development

  • The Wnt family is a group of 19 glycoproteins in humans involving a complex mechanism of signaling
  • Serious pathology may develop when these controlled mechanisms go wrong
  • The relevance of Wnt signaling in human cancers is best known for its role in colon cancer where the healthy colonic epithelia accumulates mutation in specific genes such as APC, B-catenin, K-ras and p53
29
Q

Explain the Notch pathway

A

Signals exchanged between neighboring cells through the Notch receptor and can amplify and consolidate molecular differences, which eventually dictate cell fates. Thus, notch signals c9ntrol how cells respond to intrinsic or extrinsic developmental cues that are necessary to unfold specific developmental programs.

Notch signaling is a developmental pathway in multicellular organisms involved in cell fate decisions and pattern formation during embryogenesis. Mammals possess four different notch receptors, refferred to as NOTCH1, NOTCH2, NITCH3 & NOTCH4

Apart from regulating cellular communication in embryogenesis, it also helps in stem cell growth and differentiation

Inappropriate activation of the notch pathway leads to uncontrolled proliferation, restricted differentiation and prevents apoptosis in cancer calls as observed in human malignancies in T-cell Acute lymphoblastic leukemia and breast cancer

30
Q

Explain the hedgehog pathway

A

The Hh is a 400-460 amino acid long precursor protein

  • The (HhN) amino terminal domain works as a signaling molecule, whereas the carboxy-terminal domain (HhC) has an auto-catalyzing Hint module.
  • The Hh signal transduction pathway components tightly control embryonic development, and also expressed in postnatal and adult tissues, where these components have assigned roles in the maintenance of stem cells, these is loss of one copy of SHh

conventional model of hedgehog signal reception. Smoothened-Smo(green) has an intrinsic intracellular signaling activity that is repressed by its direct interaction with Patch-Ptc(red)within plasma membrane. This repression is released when Hh binds to Ptc, with Smo undergoing a conformational change that allows it to activate its intracellular target(s)

31
Q

Explain the B-cell-specific Moloney Murine Leukemia Virus Integration Site 1(BMI1) Pathway

A

The BMI1 pathway is one of the proto-oncogenic signaling pathways like Hh, Nitch and Wnt involved in the differentiation and self-renewal mechanisms of stem cells prersistently

  • The BMI1 belongs of the Polycomb group of gene family, well-known epigenetic gene silencers, targeting the p16 and p19Arf locus which suppress cell proliferation
  • Human BMI1 gene comprises of 10 exons and is localized on chromosome 10. BMI1 gene encides a 324 amino acid long protein.
  • Overrxpression of BMI1 is critical fir the maintenance of CSCs in most of the human tumors
  • It’s expression is highly unregulated in acute myeloid leukemia, cancers of the lung, ovarie, breast and neuroblastoma. CSCs are highly enriched with BMI1
32
Q

What are the ethical issues with stem cell research and applications?

A

Stem cell research and therapies have generated ethical and contentious issues in society that must be addressed along with the scientific and medical benefits:

  • religious beliefs
  • concepts of individual rights
  • tolerance fir 7ncertainty
  • risks
  • limits 8n hie scuentific interventions should be used o alter the outcome of disease

Molecular Biology (24 decks)

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