5: Growth and Differentiation of the Epidermis Flashcards
What are the characteristics of epidermal stem cells?
Progenitor cells that can renew and give rise to differentiated progeny. Putative stem cells that self-renew robustly. Markers include B1 integrin, LRIG1, and CD46.
What is the role of the epidermal stem cell niche?
It is the tissue environment where stem cells exist, located throughout the basal layer or at the tops/bottoms of rete ridges.
How does epidermal proliferation contribute to skin health?
It involves continuous proliferation for homeostatic turnover, occurring approximately every 2 weeks. It plays a crucial role in wound healing.
What are the key features of basal cells in the epidermis?
Express Keratin 5 and 14. Show increased levels of Dsg3. Form cell-cell adhesions through desmosomes and adherens junctions, giving rise to spinous cells.
What are the characteristics of spinous cells in the epidermis?
Express Keratin 1 and 10. Show increased levels of Dsg1. Exhibit upregulation of desmosomes, leading to a spiny appearance.
What are the functions of granular cells in the epidermis?
Contain keratohyalin granules, composed of keratins, profilaggrin, and loricrin. Profilaggrin is metabolized into Natural Moisturizing Factor for hydration and UV protection. Contribute to the epidermal differentiation complex on chromosome 1q21, which includes proteins like loricrin and involucrin.
What is the structure and function of the stratum corneum?
Composed of cornified envelopes that are acellular and anuclear. The core consists of keratins surrounded by crosslinked proteins, especially loricrin. Surrounded by lipids, including crosslinked ceramides, contributed by transglutaminase.
What role do transcriptional regulators play in epidermal differentiation?
p63: Controls epidermal specification and maintains basal cell fate and proliferation. Notch: Facilitates the transition of basal cells to spinous cells. GRHL3: Involved in barrier formation and regulation of transglutaminase 1.
How do epigenetic regulators influence epidermal differentiation?
DNA methylation: Suppresses expression of differentiation genes in the basal layer (DNMT1). Histone modifications: Organize chromosomal DNA and regulate gene expression through methylation and acetylation, promoting differentiation.
What are the components of posttranscriptional regulation in epidermal differentiation?
miRNA modulate the levels/translation of a number of target mRNAs. miR-203 in spinous cells represses p63, thus ensuring proper differentiation.
IncRNA such as ANCR, recruits histone
methytransferase to certain promoters and promotes basal cell fate. TINCR promotes differentiated cell fate, stabilizing the differentiation promoting mRNAs such as Klf4 and Grhl3.
A patient presents with a defect in the Claudin1 protein. What condition might they have, and how does this defect affect the epidermis?
The patient might have neonatal ichthyosis. The Claudin1 defect disrupts tight junctions, which are essential for cell-cell adhesion, restricting fluid/ion flow, and serving as a barrier to membrane diffusion.
How would a mutation in the p63 gene affect epidermal differentiation and basal cell maintenance?
A mutation in the p63 gene would impair the control of epidermal specification, basal cell fate maintenance, and the induction of differentiation, potentially leading to defective skin barrier formation.
If a researcher observes increased Dsg1 expression in a cell, what type of epidermal cell are they likely studying?
They are likely studying spinous cells, as these cells exhibit increased Dsg1 expression and upregulation of desmosomes, giving them a spiny appearance.
What would happen to the epidermis if DNMT1 activity is inhibited in the basal layer?
Inhibiting DNMT1 would lead to the loss of DNA methylation, resulting in the expression of differentiation genes in the basal layer, disrupting the balance between proliferation and differentiation.
A patient has a mutation in the GRHL3 gene. What epidermal function might be impaired, and why?
The patient might have impaired barrier formation because GRHL3 regulates transglutaminase 1, which is crucial for forming the epidermal barrier.
How does the metabolization of profilaggrin contribute to the skin’s hydration and UV protection?
Profilaggrin is metabolized into amino acids, pyrrolidone carboxylic acid, and urocanic acid, which are components of the Natural Moisturizing Factor (NMF) that provide hydration and UV protection.
What role does Notch signaling play in the transition of basal cells to spinous cells?
Notch signaling facilitates the transition of basal cells to spinous cells, promoting differentiation within the epidermis.
What structural feature of granular cells contributes to their role in the epidermal barrier?
Granular cells contain keratohyalin granules composed of keratins, profilaggrin, and loricrin, as well as tight junctions that restrict fluid/ion flow and act as a barrier to membrane diffusion.
How does histone acetylation influence epidermal differentiation?
Histone acetylation promotes epidermal differentiation by modifying chromosomal DNA organization, making differentiation genes more accessible for transcription.
What is the significance of the epidermal differentiation complex on chromosome 1q21?
The epidermal differentiation complex on chromosome 1q21 encodes proteins like loricrin, involucrin, and late cornified envelope proteins, which are essential for the structural integrity and function of the epidermis.
How do miRNAs like miR-203 regulate epidermal differentiation?
miR-203 represses p63 in spinous cells, thereby promoting differentiation and preventing the maintenance of basal cell characteristics.
What would be the consequence of a defect in transglutaminase activity in the stratum corneum?
A defect in transglutaminase activity would impair the crosslinking of ceramides and proteins, compromising the lipid barrier and structural integrity of the stratum corneum.
How does the basal layer’s expression of Keratin 5 and 14 contribute to its function?
Keratin 5 and 14 provide structural support and are essential for the basal layer’s role in giving rise to spinous cells and maintaining cell-cell adhesions through desmosomes and adherens junctions.
What is the role of ANCR and TINCR in epidermal differentiation?
ANCR promotes basal cell fate, while TINCR promotes differentiated cell fate, ensuring proper regulation of epidermal differentiation.
How does the stratum corneum maintain its barrier function despite being acellular and anuclear?
The stratum corneum maintains its barrier function through cornified envelopes composed of keratins surrounded by crosslinked proteins (e.g., loricrin) and lipids like ceramides.
What would be the effect of a loss of methylation in basal cells?
Loss of methylation in basal cells would promote differentiation and inhibit the basal cell fate, disrupting the balance of proliferation and differentiation.
How does the epidermal stem cell niche support stem cell function?
The epidermal stem cell niche provides a tissue environment that supports stem cell self-renewal and differentiation, located throughout the basal layer or at the tops/bottoms of rete ridges.
What is the role of B1 integrin in epidermal stem cells?
B1 integrin is a marker of epidermal stem cells and plays a role in their robust self-renewal and interaction with the stem cell niche.
How does the presence of desmosomes and adherens junctions in basal cells affect their function?
Desmosomes and adherens junctions in basal cells provide strong cell-cell adhesions, essential for maintaining the structural integrity of the basal layer and its role in giving rise to spinous cells.
What would happen if profilaggrin metabolism is disrupted in granular cells?
Disruption in profilaggrin metabolism would impair the production of Natural Moisturizing Factor components, leading to reduced skin hydration and UV protection.
How does the spiny appearance of spinous cells arise?
The spiny appearance of spinous cells arises from the upregulation of desmosomes, which are cell-cell adhesion structures.
What is the function of loricrin in the stratum corneum?
Loricrin is a major protein in the cornified envelope of the stratum corneum, providing structural integrity and contributing to the barrier function.
How does urocanic acid, a metabolite of profilaggrin, contribute to skin health?
Urocanic acid contributes to skin health by being part of the Natural Moisturizing Factor, which provides hydration and UV protection.
What would be the effect of a defect in the Notch signaling pathway on epidermal differentiation?
A defect in the Notch signaling pathway would impair the transition of basal cells to spinous cells, disrupting the differentiation process.
How does the lipid composition of the stratum corneum contribute to its function?
The lipid composition, including crosslinked ceramides, contributes to the stratum corneum’s barrier function by preventing water loss and protecting against external insults.
What is the role of keratohyalin granules in granular cells?
Keratohyalin granules, composed of keratins, profilaggrin, and loricrin, play a role in forming the epidermal barrier and maintaining skin hydration.
How does the basal layer contribute to wound healing?
The basal layer contributes to wound healing through continuous proliferation and the generation of new cells to replace damaged tissue.
What would be the consequence of a defect in the epidermal differentiation complex?
A defect in the epidermal differentiation complex would impair the production of proteins like loricrin and involucrin, compromising the structural integrity and function of the epidermis.
How does transglutaminase activity affect the lipid barrier of the stratum corneum?
Transglutaminase activity crosslinks ceramides, which are essential for the lipid barrier’s integrity and function in the stratum corneum.
What is the role of DNA methylation in the basal layer?
DNA methylation suppresses the expression of differentiation genes in the basal layer, maintaining the proliferative state of basal cells.
How does the epidermis achieve homeostatic turnover?
The epidermis achieves homeostatic turnover through continuous proliferation in the basal layer, with a cycle of approximately two weeks.
What would happen if miR-203 is overexpressed in basal cells?
Overexpression of miR-203 in basal cells would repress p63, leading to premature differentiation and a loss of basal cell characteristics.
How does the presence of tight junctions in granular cells contribute to the epidermal barrier?
Tight junctions in granular cells restrict the flow of fluids and ions, acting as a barrier to membrane diffusion and contributing to the epidermal barrier.
What is the significance of the acellular and anuclear nature of the stratum corneum?
The acellular and anuclear nature of the stratum corneum allows it to serve as a durable, protective barrier without the need for active cellular processes.
How does the transition from basal cells to spinous cells affect keratin expression?
The transition from basal cells to spinous cells involves a shift from Keratin 5 and 14 to Keratin 1 and 10 expression, reflecting their differentiation.
What would be the effect of a defect in loricrin production on the stratum corneum?
A defect in loricrin production would compromise the structural integrity of the cornified envelope, weakening the barrier function of the stratum corneum.
How does the epidermis protect against UV radiation?
The epidermis protects against UV radiation through components like urocanic acid, a metabolite of profilaggrin, which absorbs UV light.
What is the role of late cornified envelope proteins in the epidermis?
Late cornified envelope proteins contribute to the structural integrity and barrier function of the epidermis by being part of the cornified envelope.
Basal cells are defined by basement membrane attachment, presence of hemidesmosomes and the expression of keratins ___ and ___.
5 and 14
Dsg 3 and Plakophilin 2 are highly expressed in these epidermal cells.
Basal cells
Dsg1 and Plakophilin 1 are highly expressed in these epidermal cells.
Differentiated epidermal cells
Keratin ___ and ___ mark all differentiated cell layers.
1 and 10
Loricin and filaggrin are expressed in these epidermal cells.
Upper spinous and granular cells.
_____ and _____ mark the granular cells
Tight junctions and keratohyaline granules
These Type 1 keratins are expressed in the suprabasal epidermis.
K9, K10
Type 1 keratin expressed in the cornea?
K12
Type 1 keratin in the oral mucosa?
K13
Type 1 keratins in complex epithelia?
K14, K15
Type 1 keratins in epithelial appendages?
K16, K17
Type 1 keratin in simple epithelia?
K18
Type 1 keratin with broad distribution?
K19
Type 1 keratin in gut epithelium?
K20
Type 1 keratin in the pancreas?
K23
Type 1 keratin in the inner root sheath (hair follicles)?
K25-K28
Type 1 keratin in the hair shaft?
K31-K40
Type 2 keratins in the suprabasal epidermis?
K1, K2
Type 2 keratin in the suprabasal cornea?
K3
Type 2 keratin in the suprabasal oral mucosa?
K4
Type 2 keratin in the basal layer of complex epithelia?
K5
Type 2 keratins in epithelial appendages?
K6a, K6b
Type 2 keratin in the skin?
K6c, K79
Type 2 keratin in simple epithelia?
K7, K8
Type 2 keratins in the inner root sheath?
K71-74
Type 2 keratin in the companion layer?
K75
Type 2 keratin in the oral mucosa?
K76
Type 2 keratin in sweat gland ducts?
K77
Type 2 keratins in the tongue?
K78, K80
Type 2 keratin in the hair shaft?
K81-K86
Target epidermal gene and affected epidermal cell type in EBS?
Target epidermal gene and affected epidermal cell type in EBS with mottled pigmentation?
Target epidermal gene and affected epidermal cell type in EBS with limb girdle muscular dystrophy?
Target epidermal gene and affected epidermal cell type in Dowling-Degos disease?
Target epidermal gene and affected epidermal cell type in Epidermolytic hyperkeratosis?
Target epidermal gene and affected epidermal cell type in Ichthyosis hystrix (Curth-Macklin)?
Target epidermal gene and affected epidermal cell type in Ichthyosis bullosa of Siemens palmoplantar keratodermas?
What keratin-based, inherited skin bullous disease affects the basal keratinocytes, spinous keratinocytes and granular keratinocytes?
What are regulators of epidermal differentiation found in the basal, spinous, and granular layer?
Keratohyaline granules are composed of what 3 proteins?
Keratins
Profilaggrin
Loricrin
_____ highly crosslinks keratins and loricrin to the plasma membrane to generate cornified envelopes.
Transglutaminase
Mutation of TG1 results to?
Lamellar ichthyosis
It is also called the natural moisturizing factor (NMF) and provides hydration and UV protection.
Urocanic acid
Fluid loss is prominent in this epidermal cell layer.
Granular
These are cell to cell adhesions that
restrict the flow of fluids and ions.
Tight junctions
These are found within the core of tight junctions.
Claudins
These are acellular and anuclear structures that are the final products of terminal differentiation in the epidermis.
Cornified envelopes
It is the #1 component of cornified
envelope).
Loricrin
How long is cell transit from the basal layer to the stratum corneum?
14 days
How long is cell transit from the stratum corneum to desquamation?
14 days
The epidermis replenishes itself every ___ weeks.
2
How long is cell transit from the basal layer to desquamation?
28 days
This is the issue microenvironment in
which stem cells normally exist.
Niche
These are progenitor cells that can
both renew themselves and give rise
to differentiated progeny over an
extended time period.
Stem cells
Cells containing ___, ___ and ___ have higher self-renewing capacity and tends to form clusters in intact skin. They are ppresent in isolated basal cells in mice.
B1 Integrin, LRIG1 and CD46
The niche for stem cells in the
human interfollicular epidermis is
not clear as various studies suggested that they are located dispersed throughout the _____ or at the _____.
Basal layer
Tops or bottoms of rete ridges.
Major developmental signaling
pathways to regulate epidermal proliferation (4)?
- Wnt
- Notch
- Yap
- Hedgehog
Major downstream targets to regulate growth and entry into and passage through the cell cycle?
- Ras-MAPK
- PI3K/AKT/PTEN
These keratins are acidic, wth LOW
molecular weight.
Type 1 Keratins
These keratins are basic, wth HIGH
molecular weight.
Type 2 Keratins
Defects in Claudin 1 causes?
Neonatal ichthyosis
Cell death occurs in what epidermal layer?
Granular layer, which eventually forms the cornified envelope.
What are transcriptional regulators of epidermal differentiation (3)?
P63
KLF4
Notch signaling
What transcriptional regulator?
P63
What transcriptional regulator?
KLF4
What transcriptional regulator?
Notch signaling
_____ control the organization and/or accessibility of chromatin for transcriptional regulation.
Epigenetic regulators
What epigenetic regulator?
DNA methylation
What epigenetic regulator?
Histone / histone modifications
E.g.
Methylation of many epidermal genes causes repression of expression in the basal cells while loss of methylation promotes differentiation. Methylation also inhibits other cell’s fates.
Acetylation is also essential in epidermal differentiation as histone deacetylases binds to the same gene promoters that p63 represses.
What chromatin remodeler?
SWI/SNF complex
What chromatin remodeler?
Satb and Brg1
This posttranscriptional regulator when increased, causes premature differentiation. Therefore it is expressed at low levels in the basal cells.
GRHL3
