1
Q

What is the role of the Nail Proximal Fold (NPF) in nail structure?

A

The Nail Proximal Fold (NPF) results from the inward and ventral folding of the skin epidermis. Nail layers beyond the NPF do not have a granular layer, as normal epidermal differentiation ceases beyond where the eponychium folds inward.

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2
Q

What are the two types of nail stem cells mentioned, and how do they differ?

A

The two types of nail stem cells are:
1. Nail Proximal Fold Stem Cells (NPFSC) - These are slow cycling stem cells.
2. Nail Stem Cells (NSC) - These are fast cycling stem cells.

The primary difference lies in their cycling rates, with NPFSC being slow and NSC being fast.

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3
Q

What is the function of onychocytes in the nail matrix?

A

Onychocytes are actively proliferating cells that compose the nail matrix. They play a crucial role in nail growth and regeneration.

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4
Q

Where are nails located in relation to the phalanx of fingers and toes?

A

Nails are located on the distal phalanx of each finger and toe.

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5
Q

What is the significance of the eponychium in nail anatomy?

A

The eponychium, or cuticle, is an extension of the distal phalanx skin epidermis that protects the nail bed and plays a role in the overall structure of the nail.

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6
Q

How does the nail proximal fold (NPF) contribute to nail anatomy?

A

The NPF results from the inward and ventral folding of the skin epidermis. It lacks a granular layer, as normal epidermal differentiation ceases beyond the eponychium.

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7
Q

What is the function of the eponychium in nail anatomy?

A

The eponychium, or cuticle, is an extension of the distal phalanx skin epidermis that protects the nail matrix from external contaminants.

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8
Q

How do nail stem cells (NSC) differ from nail proximal fold stem cells (NPFSC) in terms of cycling?

A

Nail stem cells (NSC) are classified as fast cycling, while nail proximal fold stem cells (NPFSC) are slow cycling. This difference affects their roles in nail regeneration and maintenance.

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9
Q

What is the significance of onychocytes in the nail matrix?

A

Onychocytes are actively proliferating cells that compose the nail matrix. They play a crucial role in nail growth and regeneration by contributing to the formation of the nail plate.

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10
Q

Describe the anatomical location of nails in relation to the phalanx.

A

Nails are located on the distal phalanx of each finger and toe, providing protection and support to the tips of the digits.

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11
Q

What happens to epidermal differentiation beyond the nail proximal fold (NPF)?

A

Epidermal differentiation ceases beyond the nail proximal fold (NPF), resulting in nail layers that do not have a granular layer, which is typical in normal epidermal differentiation.

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12
Q

How does the nail matrix contribute to nail regeneration?

A

The nail matrix, which is a continuation of the nail proximal fold (NPF), contains actively proliferating onychocytes that are essential for nail growth and regeneration.

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13
Q

What is the relationship between the nail matrix and the eponychium?

A

The nail matrix is located beneath the eponychium and is responsible for producing the nail plate. The eponychium serves as a protective barrier for the nail matrix.

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14
Q

Explain the significance of the keratogenous zone in nail structure.

A

The keratogenous zone is where keratinocytes differentiate and deposit cells into the overlying nail plate, playing a vital role in the formation and integrity of the nail.

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15
Q

What is the clinical relevance of understanding nail anatomy and stem cell function?

A

Understanding nail anatomy and the function of stem cells is crucial for diagnosing and treating nail disorders, as well as for developing regenerative therapies for nail injuries.

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16
Q

What is the Keratogenous Zone (KZ) and its role in nail growth?

A

The Keratogenous Zone (KZ) is the area on top of the matrix where matrix cells differentiate, flatten out, die, and are deposited on the overlying nail plate, contributing to nail growth.

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17
Q

What are corneocytes and their function in the nail plate?

A

Corneocytes are flattened anucleated cells present in the nail plate that serve as a protective covering, preventing trauma to the tips of the digits. They are formed from differentiated onychocytes found in the matrix.

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18
Q

What is the significance of the nail matrix in nail plate production?

A

The nail matrix is believed to be largely responsible for nail plate production. Studies suggest it produces the bulk of the nail plate, while the nail bed contributes to its thickness and mass, allowing for distal movement as the nail grows.

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19
Q

What did Zaias and Alvarez discover about nail cell labeling in their study?

A

Zaias and Alvarez used tritiated glycine to mark and follow nail cells in squirrel monkeys, finding that the uptake of the label moves from the matrix to the nail plate over time, indicating that the nail bed is not a significant source of nail plate due to inactivity.

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20
Q

What are the two pools of stem cells in the nail organ and their roles?

A

The two pools of stem cells in the nail organ are involved in homeostasis and regeneration. Upon activation, these stem cells differentiate into transit amplifying progenitor cells (TA Cells) that rapidly divide and differentiate into cells needed for regeneration or repair.

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21
Q

A patient presents with a nail injury that has damaged the nail matrix. What is the expected impact on nail growth and why?

A

The nail matrix is responsible for producing the bulk of the nail plate. Damage to the matrix can impair nail growth or lead to abnormal nail formation because the matrix contains actively proliferating onychocytes that differentiate into the nail plate.

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22
Q

In an experiment, tritiated glycine is used to trace nail cell activity. What does the movement of the label from the matrix to the nail plate indicate?

A

The movement of the label from the matrix to the nail plate indicates that the matrix is the primary source of nail plate production, as the labeled cells are actively incorporated into the growing nail plate.

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23
Q

What experimental evidence supports the role of the nail matrix as the primary source of nail plate production?

A

Zaias and Alvarez used tritiated glycine to trace nail cells in squirrel monkeys. They found that the label moved from the matrix to the nail plate over time, with minimal incorporation in the nail bed, dismissing it as a source of nail plate production.

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24
Q

What is the role of the keratogenous zone in nail formation?

A

The keratogenous zone, located on top of the matrix, is where matrix cells differentiate, flatten out, die, and are deposited onto the overlying nail plate, contributing to its formation.

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25
Q

What is the role of the lunula in nail anatomy?

A

The lunula is the visible white crescent-shaped base of the nail, representing the distal part of the matrix where active cell proliferation occurs.

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26
Q

How does the nail bed contribute to nail plate production?

A

The nail bed contributes to the nail plate’s thickness, mass, and ventral portion, facilitating the distal movement of the nail plate as it grows.

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27
Q

What is the function of corneocytes in the nail plate?

A

Corneocytes are flattened, anucleated cells in the nail plate that provide a hard, protective covering, preventing trauma to the tips of the digits.

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28
Q

What is the role of transit amplifying (TA) progenitor cells in nail regeneration?

A

TA progenitor cells, derived from activated stem cells, rapidly divide and differentiate into cells needed for nail regeneration or repair.

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29
Q

How does the nail matrix differ from the nail bed in terms of function?

A

The nail matrix is the primary source of nail plate production, while the nail bed contributes to the nail plate’s thickness, mass, and ventral portion, aiding its distal movement.

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30
Q

What is the role of the onychodermal band in nail anatomy?

A

The onychodermal band is a part of the nail that contributes to the structural integrity and attachment of the nail plate to the underlying tissue.

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31
Q

How does the nail plate protect the digits?

A

The nail plate, composed of hard corneocytes, serves as a protective covering, preventing trauma to the tips of the digits.

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32
Q

What is the role of the Keratogenous Zone (KZ) in nail growth?

A

The Keratogenous Zone (KZ) is the area on top of the matrix where matrix cells differentiate, flatten out, die, and are deposited onto the overlying nail plate.

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33
Q

What are corneocytes and where are they found in the nail structure?

A

Corneocytes are flattened anucleated cells present in the nail plate, specifically overlying the distal phalanx, and are formed from differentiated onychocytes found in the matrix.

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34
Q

What is the significance of the lunula in nail anatomy?

A

The lunula is the white crescent-shaped base that is the visible part of the nail matrix, indicating the area of active nail growth.

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35
Q

How does the nail bed contribute to nail plate production?

A

The nail bed, composed of a basal layer and one or two layers of suprabasal post-mitotic keratinocytes, contributes to the nail plate’s thickness and mass, allowing for distal movement as the nail grows.

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36
Q

What did Zaias and Alvarez discover about nail cell labeling in their study?

A

Zaias and Alvarez found that the uptake of the tritiated glycine label moves from the matrix to the nail plate over time, with only small amounts incorporated into the nail bed, suggesting the nail bed is inactive in nail plate production.

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37
Q

According to Lewis’s theory, how many layers does the nail consist of and what are they?

A

Lewis proposed that the nail consists of three layers: the proximal nail fold (superficial layer of the dorsal nail), the matrix (intermediate nail), and the nail bed (deep ventral nail).

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38
Q

What method is used to localize slow cycling stem cells in tissues?

A

The slow cycling property radioactive labeling method, also known as the slow pulse chase, uses Tritiated Thymidine (H-Thymidine) as a marker for slow cycling stem cells.

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39
Q

What is the primary conclusion regarding the nail matrix’s role in nail plate production?

A

The primary conclusion is that the nail matrix is solely responsible for nail plate production, as it produces the bulk of the nail plate.

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40
Q

What are the other parts of the nail besides the nail plate and matrix?

A

Other parts of the nail include lateral nail folds (paronychium), grooves, hyponychium, and the onychodermal band.

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41
Q

What are slow-cycling label retaining cells (LRCs) and how are they identified in research?

A

Slow-cycling label retaining cells (LRCs) are identified by their retention of markers like Thymidine, which is incorporated into the DNA of dividing cells. Research by Costarelis and coworkers used the slow pulse chase method to determine the presence of LRCs in hair follicle bulges and the Cornea’s Limbus, theorizing that these LRCs are stem cells of the hair follicle and Cornea.

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42
Q

What role does BMP signaling play in nail formation and differentiation?

A

BMP signaling is essential for proper nail formation and differentiation. It guides Nail Progenitor Stem Cells (NPFSCs) toward nail differentiation and maintains the LRC characteristics of NPFSCs. Absence of BMP signaling can lead to several issues, including less matrix cell proliferation, absence of the Keratogenous zone, and loss of LRCs.

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43
Q

What findings were reported by Sellheyer and coworkers regarding the expression of hair follicle stem cell markers in the nail fold?

A

Sellheyer and coworkers found that the ventral proximal nailfold expresses hair follicle stem cell (hfSC) markers such as K15, K19, and PHLDA, with very few Ki67+ cells, indicating a low level of cell proliferation in this area.

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44
Q

What are the consequences of BMP signaling absence in nail development?

A

The absence of BMP signaling can lead to:
1. Less matrix cell proliferation
2. Absent Keratogenous zone
3. No proper nail plate differentiation
4. Hyperplasia of the nail bed
5. Loss of LRCs
6. Ectopic granular layer extension over the whole nail plate
7. Ectopic K1 and Loricrin markers instead of AE13.

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45
Q

A researcher observes that BMP signaling is absent in a mouse model. What abnormalities in nail structure and function might be expected?

A

Absence of BMP signaling can lead to reduced matrix cell proliferation, absence of the keratogenous zone, improper nail plate differentiation, hyperplasia of the nail bed, loss of label-retaining cells (LRCs), and ectopic granular layer extension over the nail plate.

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46
Q

How does the presence of K15+ cells in the nail proximal fold contribute to nail regeneration?

A

K15+ cells in the nail proximal fold are slow-cycling bifunctional stem cells that contribute to both nail structure and the perinail epidermis. Upon regeneration, these cells actively deliver progeny to the nail matrix and differentiate into the nail plate.

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47
Q

How does BMP signaling guide nail proximal fold stem cells (NPFSCs)?

A

BMP signaling guides NPFSCs toward nail differentiation and maintains their label-retaining cell (LRC) characteristics. Its absence leads to multiple abnormalities, including loss of LRCs and improper nail plate differentiation.

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48
Q

What experimental method can be used to identify slow-cycling cells in the nail, and how does it work?

A

The radioactive labeling method using tritiated thymidine (H-Thymidine) identifies slow-cycling cells. Thymidine is incorporated into newly synthesized DNA, and slow-cycling cells retain this marker after division, making them label-retaining cells (LRCs).

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49
Q

What abnormalities occur in the nail plate when BMP signaling is disrupted?

A

Disruption of BMP signaling leads to absent keratogenous zones, improper nail plate differentiation, hyperplasia of the nail bed, and ectopic granular layer extension over the nail plate.

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50
Q

What is the role of LRCs in nail regeneration?

A

Label-retaining cells (LRCs) are slow-cycling cells that retain markers like H-Thymidine. They contribute to nail regeneration by differentiating into progenitor cells needed for repair.

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51
Q

What is the significance of Thymidine in identifying slow-cycling label retaining cells (LRCs)?

A

Thymidine is incorporated into the newly synthesized DNA of dividing cells. Slow-cycling cells retain this marker after a period of division, allowing researchers to identify them as LRCs.

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52
Q

How did Costarelis and coworkers utilize the slow pulse chase method in their research on LRCs?

A

They used the slow pulse chase method to determine the presence of LRCs in the hair follicle bulge, which can be stimulated by a tumor promoter, and in the Cornea’s Limbus, theorizing that these LRCs are stem cells of the hair follicle and Cornea.

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53
Q

What is the marker retained by slow-cycling cells after division?

A

Slow-cycling cells retain a specific marker after a period of division, allowing researchers to identify them as LRCs.

54
Q

How did Costarelis and coworkers utilize the slow pulse chase method in their research on LRCs?

A

They used the slow pulse chase method to determine the presence of LRCs in the hair follicle bulge and in the Cornea’s Limbus.

55
Q

What role do Bromodeoxyuridine (BrdU) and Tetracycline-induced histone 2B-green fluorescent protein (H2B-GFP) antibodies play in immunological histology?

A

BrdU and H2B-GFP antibodies are used to co-localize potential markers through immunological histology.

56
Q

What findings did Sellheyer and coworkers report regarding hair follicle stem cell markers in the nailfold?

A

They found that the ventral proximal nailfold expresses hair follicle stem cell markers (e.g., K15, 19, and PHLDA) and has very few Ki67+ cells.

57
Q

What is the significance of K15 labeled cells in the context of nail LRCs?

A

K15 labeled cells exhibit bifunctional stem cell characteristics, contributing to both nail structure and the perinail epidermis.

58
Q

How do K15 derived cells contribute to nail regeneration?

A

K15 derived cells actively deliver progeny to the nail matrix and differentiate into the nail plate.

59
Q

What is the role of BMP signaling in nail development?

A

BMP signaling is required for proper nail formation and differentiation.

60
Q

What are the consequences of BMP signaling absence in nail development?

A

Absence of BMP signaling can lead to less matrix cell proliferation, absent Keratogenous zone, and loss of LRCs.

61
Q

What role does BMP signaling play in nail differentiation?

A

BMP signaling is crucial for proper nail differentiation, similar to its role in hair follicle differentiation.

62
Q

What method did Takeo and coworkers use to label keratinocytes in the nail and skin epidermis?

A

They used the K14 promoter Cre-ER to mark keratinocytes of the basal layer of skin and nail epidermis.

63
Q

What were the findings regarding LacZ+ descendants of K14 labeled nail epithelial cells over a 5-month period?

A

The findings demonstrated that LacZ+ descendants extended linearly and distally, emerging only from the proximal matrix.

64
Q

What characteristics do proximal matrix cells exhibit in terms of colony forming ability and self-renewal?

A

Proximal matrix cells have the highest colony forming ability in vivo and in vitro.

65
Q

How does Wnt signaling differ between proximal and distal matrix cells in nail growth?

A

Proximal matrix cells have downregulated Wnt signaling compared to distal matrix cells.

66
Q

What is the significance of B-catenin in Wnt signaling related to nail epithelium?

A

B-catenin is an essential mediator of Wnt signaling; its removal leads to an epithelium devoid of AE13.

67
Q

What role does Wnt signaling play in nail differentiation?

A

Wnt signaling is crucial for nail differentiation, particularly in the distal matrix.

68
Q

How does the absence of B-catenin affect nail epithelium and differentiation?

A

The absence of B-catenin results in an epithelium devoid of AE13 and shows characteristics of the NSC region.

69
Q

How do proximal matrix cells contribute to nail growth?

A

Proximal matrix cells express K14, K17, and Ki67, giving rise to distal matrix cells with Wnt activation.

70
Q

What is the significance of AE13 as a marker in nail differentiation?

A

AE13 is a marker of keratinized nail plate cells; its absence indicates a lack of proper nail differentiation.

71
Q

What experimental evidence supports the role of Wnt signaling in nail differentiation?

A

Takeo and coworkers showed that proximal matrix cells with downregulated Wnt signaling give rise to distal matrix cells with Wnt activation.

72
Q

What is the significance of Ki67 expression in proximal matrix cells?

A

Ki67 is associated with cell proliferation; its expression indicates high proliferative activity in proximal matrix cells.

73
Q

What is the role of B-catenin in Wnt signaling for nail differentiation?

A

B-catenin is necessary for nail differentiation, activating pathways leading to keratinized nail plate formation.

74
Q

What method did Takeo and coworkers use to label keratinocytes in the nail and skin epidermis?

A

Takeo and coworkers used the K14 promoter Cre-ER to mark keratinocytes of the basal layer.

75
Q

What were the findings regarding the descendants of LacZ+ labeled nail epithelial cells over a 5-month period?

A

The findings showed that LacZ+ descendants extended linearly and distally, emerging only from the proximal matrix.

76
Q

What characteristics do proximal matrix cells exhibit in terms of colony forming ability and self-renewal?

A

Proximal matrix cells exhibit the highest colony forming ability in vivo and in vitro.

77
Q

What is the role of B-catenin in Wnt signaling related to nail differentiation?

A

B-catenin is an essential mediator of Wnt signaling; its removal leads to an epithelium devoid of AE13.

78
Q

What markers are expressed in proximal matrix cells and what is their significance?

A

Proximal matrix cells express K14, K17, and Ki67, indicating the presence of rapidly dividing self-renewing cells.

79
Q

What happens to the nail epithelium when B-catenin is removed?

A

Removal of B-catenin results in an epithelium devoid of AE13 and shows characteristics of the NSC region.

80
Q

What is the role of Lgr6 in the nail matrix?

A

Lgr6 is a mediator of Wnt signaling localized within the proximal nail matrix, serving as a nuclear marker specific to nail stem cells.

81
Q

How do slow cycling bifunctional BPFSCs contribute to nail structure?

A

Slow cycling bifunctional BPFSCs function primarily for nail structure and give rise to the perinail epidermis.

82
Q

What is the significance of Wnt/B-catenin signaling in digit regeneration?

A

Wnt/B-catenin signaling from the epithelium is necessary for digit regeneration.

83
Q

What happens to digit regeneration if amputation occurs proximal to the NSC niche?

A

If amputation occurs proximal to the NSC niche, digit regeneration cannot be restored.

84
Q

What are the consequences of Wnt deletion in B-catenin knockout mice?

A

Wnt deletion in B-catenin knockout mice results in a lack of nail differentiation and blocks bone regeneration.

85
Q

What is the significance of Lgr6 expression in the proximal nail matrix?

A

Lgr6 is a nuclear marker specific to nail stem cells in the proximal matrix, mediating Wnt signaling.

86
Q

How do slow-cycling bifunctional nail fold stem cells differ from rapidly cycling unipotent nail stem cells?

A

Slow-cycling bifunctional nail fold stem cells contribute to nail structure, while rapidly cycling unipotent nail stem cells are responsible for increased proliferative activity.

87
Q

What is the role of Lgr6 in the proximal nail matrix?

A

Lgr6 is a mediator of Wnt signaling localized within the proximal nail matrix.

88
Q

What is the significance of Wnt/B-catenin signaling in digit regeneration?

A

Wnt/B-catenin signaling from the epithelium is essential for digit regeneration.

89
Q

What are the characteristics of rapidly cycling unipotent NSCs in the proximal nail matrix?

A

Rapidly cycling unipotent NSCs are characterized as K14+, K17+, and Ki67+ cells.

90
Q

What is the effect of Wnt deletion in B-catenin knockout mice on nail differentiation?

A

Wnt deletion in B-catenin knockout mice results in a lack of nail differentiation.

91
Q

How does nail transplantation affect digit regeneration?

A

Nail transplantation after amputation can induce ectopic bone differentiation.

92
Q

What is the relationship between Wnt pathway activation and blastema innervations?

A

Wnt pathway activation promotes blastema innervations through semaphorin 5a.

93
Q

What is the role of BMP signaling in the differentiation of BPFSCs?

A

BMP signaling guides the differentiation of slow cycling bifunctional BPFSCs toward their specific functions.

94
Q

What is the clinical significance of the nail epithelium in digit regeneration?

A

The nail epithelium is crucial for digit regeneration as it provides a regenerative environment.

95
Q

What is the role of Sema5a in digit regeneration after amputation?

A

Sema5a is necessary for FGF2 expression, promoting the proliferation of osteoblasts.

96
Q

What are the steps involved in the digit regeneration mechanisms?

A
  1. Formation of distal matrix for Wnt activation 2. Sema5a activation via Wnt for innervation 3. Innervation stimulates FGF-2 stimulation.
97
Q

How do Lgr6 expressing cells contribute to digit regeneration?

A

Lgr6 is broadly expressed in a subset of cells in the digit tip, contributing to blastema formation.

98
Q

What clinical correlation is associated with inherited anonychia?

A

Inherited anonychia is associated with severe hypoplasia of the nails due to mutations in R-spondin 4.

99
Q

A patient has a mutation in R-spondin 4 (Rspo4). What clinical condition might they present with?

A

The patient might present with inherited anonychia, characterized by severe hypoplasia of the nails.

100
Q

Describe the sequence of events necessary for digit regeneration after amputation.

A
  1. Formation of the distal matrix for Wnt activation. 2. Activation of Sema5a via Wnt for innervation. 3. Innervation stimulates FGF-2 expression.
101
Q

What happens to nail regeneration if amputation occurs proximal to the NSC niche?

A

If amputation occurs proximal to the NSC niche, digit regeneration cannot be restored.

102
Q

What is the clinical significance of Sema5a in digit regeneration?

A

Sema5a, activated via Wnt signaling, is necessary for innervation.

103
Q

What is GF-2 expression’s role in digit regeneration?

A

GF-2 expression promotes osteoblast proliferation and Runx2 progenitors, leading to coupled digit regeneration.

104
Q

What happens to nail regeneration if amputation occurs proximal to the NSC niche?

A

If amputation occurs proximal to the NSC niche, digit regeneration cannot be restored, even with B-catenin stabilization. However, distal matrix regeneration and blastema cell formation for innervation may still occur.

105
Q

What is the clinical significance of Sema5a in digit regeneration?

A

Sema5a, activated via Wnt signaling, is necessary for innervation, which stimulates FGF-2 expression. FGF-2 promotes osteoblast proliferation and Runx2 progenitors, leading to digit regeneration.

106
Q

What abnormalities might be observed in Lgr6-deficient mice?

A

Lgr6-deficient mice exhibit defects in both nail and bone regeneration, as Lgr6 contributes to blastema formation and is broadly expressed in the digit tip.

107
Q

How does the nail epithelium influence digit regeneration after injury?

A

The nail epithelium creates a regenerative environment for digit regeneration through Wnt/B-catenin signaling, which is necessary for forming the distal matrix and promoting bone and digit regeneration.

108
Q

What is the role of FGF-2 in digit regeneration?

A

FGF-2, stimulated by Sema5a-mediated innervation, promotes osteoblast proliferation and Runx2 progenitors, leading to bone and digit regeneration.

109
Q

How does the absence of Wnt signaling affect blastema formation in digit regeneration?

A

The absence of Wnt signaling blocks blastema formation, preventing innervation and subsequent FGF-2 expression, which are necessary for bone and digit regeneration.

110
Q

What is the clinical implication of denervation in digit regeneration?

A

Denervation suppresses blastema growth, which is necessary for innervation and activation of FGF-2, ultimately impairing digit regeneration.

111
Q

What is the role of Sema5a in digit regeneration after amputation?

A

Sema5a is necessary for FGF2 expression, which promotes the proliferation of osteoblasts and Runx2 progenitors, leading to coupled digit regeneration. Deletion of Wnt downregulates Sema5a three weeks after amputation, and innervation via Sema5a is crucial for this process.

112
Q

How does innervation affect FGF2 stimulation in digit regeneration?

A

Innervation stimulates FGF2 activation, which is essential for bone and digit regeneration. Denervation suppresses blastema growth necessary for the activation of FGF2.

113
Q

What sequence of events is involved in digit regeneration according to the provided mechanisms?

A
  1. Formation of Distal matrix for Wnt activation
  2. Sema5a activation via Wnt for innervation
  3. Innervation stimulates FGF-2 stimulation for bone and digit regeneration.
114
Q

What is the significance of Lgr6 expressing cells in digit regeneration?

A

Lgr6 expressing cells are broadly present in a subset of cells in the digit tip, including bone osteoblasts and eccrine sweat glands, contributing to blastema formation. Lgr6 deficient mice exhibit defects in both nail and bone regeneration.

115
Q

What clinical correlation is associated with inherited anonychia?

A

Inherited anonychia is associated with severe hypoplasia of the nails due to mutations in R-spondin 4 (Rspo4), which is implicated in Wnt signaling.

116
Q

The _____ creates a border between skin epidermis and nail organ at the dorsal limit of the nail proximal fold (NPF), forming a protective seal.

A

eponychium

117
Q

The _____ forms after skin epidermis bends inward ventrally at the eponychium’s border and becomes
the nail epidermis, which localizes _____, which actively deliver
progeny to the perinail epidermis and nail matrix along with differentiated nail plate upon nail regeneration.

A

NPF

slow-cycling bifunctional nail proximal
fold stem cells (NPFSCs)

118
Q

The _____, a ventral continuation of the proximal fold after it bends dorsally and distally, is composed of actively proliferating cells called _____. In the _____, ____ are located, whose
differentiation is coupled directly with the ability to orchestrate digit regeneration.

A

matrix
onychocytes

proximal nail matrix
fast-proliferating nail stem cells

119
Q

Nail matrix differentiates, forming the
_____, which finally deposit cells into the overlying nail plate.

A

keratogenous zone

120
Q

_____ is the most distal part of the nail epithelium located peripherally to the nail bed, and beneath the nail plate at the junction between the free edge and the skin epidermis of the fingertip, it forms a seal that protects the nail bed.

A

Hyponychium

121
Q

Identify the parts of the human nail.

122
Q

Identify the two stem cell populations of the nail and their markers (including the nail plate).

123
Q

Proximal matrix cells possesses characteristics of undifferentiated epidermal cells expressing _____ and _____ with highly proliferative _____ marker.

A

keratin 17 (K17), K14
Ki67

124
Q

_____, a nuclear mediator of Wnt signaling, and _____ were not expressed in the proximal end of
NSCs, but several keratins that contained a TCF1 and LEF1 consensus binding site were upregulated in the
distal matrix, thus suggesting direct involvement of Wnt signaling in nail differentiation.

A

Tcf1 (also known as hepatocyte nuclear factor 1a)
Wls (Wntless homologue)

125
Q

Nail stem cells (NSCs) in the proximal matrix give rise to distal matrix cells with _____ under homeostatic conditions.

A

Wnt activation (Wntless)

126
Q

Wntless activation in nail epithelium is required to promote _____, which is necessary for _____ expression in the regenerating nail epithelium. Subsequently, it promotes proliferation of _____, ultimately leading to digit regeneration.

A

blastema innervations
Fgf2
Runx2-positive mesenchymal cells

127
Q

Affected families with inherited anonychia have severe hypoplasia of the nails in which mutations in _____, which is implicated in the Wnt signaling pathway.

A

R-spondin 4 (Rspo4)

128
Q

Marker for keratinized nail plate cells?

129
Q

T or F: β-catenin stabilization in the nail epithelium does not promote
digit regeneration after amputation proximal to the NSC niche.

130
Q

_____ expression is not only limited to the nail matrix but is more broadly expressed within a subset of cells in the digit tip, namely, in the _____ and _____. Therefore, cells expressing this signal not only mark NSC epithelium but also contribute to the blastema, which suggests not only direct but also a potential indirect role for this signal during digit-tip regeneration.

A

Lgr6

bone osteoblasts
eccrine sweat glands