Copy of embryology of the skin

Embryology of the skinEmbryology of the skin

• Dr Mesfin HunegnawDr Mesfin Hunegnaw

Consultant Dermatologist & Consultant Dermatologist & VenerologistVenerologist

AAU, Medical facultyAAU, Medical faculty

Dept. of DermtovenerologyDept. of Dermtovenerology

The skin of the embryo begins to form during the first 20 The skin of the embryo begins to form during the first 20 to 30 days of embryonic life, the period of active to 30 days of embryonic life, the period of active organogenesis in human development.organogenesis in human development.

The skin arises by the juxtaposition of two major The skin arises by the juxtaposition of two major embryological elements: embryological elements:

The prospective epidermisThe prospective epidermis, originates from a surface , originates from a surface area of the early gastrula; ectoderm. area of the early gastrula; ectoderm.

The prospective mesodermThe prospective mesoderm, which is brought into , which is brought into contact with the inner surface of the epidermis. contact with the inner surface of the epidermis.

The neural crestThe neural crest also makes contribution to the skin: also makes contribution to the skin: pigment cells.pigment cells.

The periderm:The periderm:In about the third week of fetal life, the epidermis consists In about the third week of fetal life, the epidermis consists

of a single layer of undifferentiated, glycogen-filled, a of a single layer of undifferentiated, glycogen-filled, a single layer of cells.single layer of cells.

Present only in prekeratinized, developing skin Present only in prekeratinized, developing skin sloughed to amniotic fluid. sloughed to amniotic fluid.

In a 4- to 6-week-old fetus, two layers of cells can be In a 4- to 6-week-old fetus, two layers of cells can be distinguished, the distinguished, the periderm or epitrichial layer and periderm or epitrichial layer and a stratum germinativum.a stratum germinativum.

Between 8 and 11 weeks (CRL 26-50mm) a middle layer Between 8 and 11 weeks (CRL 26-50mm) a middle layer starts to form.starts to form.

Glycogen is abundant in all layers, and a few microvillous Glycogen is abundant in all layers, and a few microvillous projections occur at the surface of the periderm. projections occur at the surface of the periderm.

Desmosomal proteins dvp. in the basal Desmosomal proteins dvp. in the basal keratinocytes at 10 wks.keratinocytes at 10 wks.

Basal and periderm cells are morphologically similar. Basal and periderm cells are morphologically similar. BBoth are nucleated, divide mitotically, contain keratin oth are nucleated, divide mitotically, contain keratin

filaments and large amounts of glycogen in the filaments and large amounts of glycogen in the cytoplasm, and joined by desmosomes. cytoplasm, and joined by desmosomes.

Periderm cells, are larger in diameter and have more Periderm cells, are larger in diameter and have more marginated heterochromatin.marginated heterochromatin.

Periderm cells undergo Periderm cells undergo multiplication multiplication (only in the first (only in the first trimester) andtrimester) and enlargement enlargement..

Nor do keratinize .Nor do keratinize .

They do not express the differentiation-specific keratins or They do not express the differentiation-specific keratins or filaggrin (the hallmarks of a keratinized epidermal cell). filaggrin (the hallmarks of a keratinized epidermal cell).

The periderm undergoes morphologic change that reflects The periderm undergoes morphologic change that reflects changes in function.changes in function.

The cells are modified at the surface facing the amniotic The cells are modified at the surface facing the amniotic cavity first by microvillicavity first by microvilli large single blebs large single blebs multiple multiple blebs.blebs.

The modifications evident in the late first trimester and The modifications evident in the late first trimester and early second trimester greatly expand the surface area early second trimester greatly expand the surface area of the skin in contact with the amniotic fluid.of the skin in contact with the amniotic fluid.

Toward the end of the second trimester, the blebs flatten Toward the end of the second trimester, the blebs flatten and regress.and regress.

Periderm FunctionsPeriderm Functions? ? It serves as a secretory epithelium,It serves as a secretory epithelium,

Transports substances from the amniotic fluid across the Transports substances from the amniotic fluid across the skin. skin.

Protect the cells of the developing “epidermis proper.” Protect the cells of the developing “epidermis proper.”

Osmoregulation.Osmoregulation.

Other epidermal cellsOther epidermal cells

Langerhans cellsLangerhans cells are present in fetal epidermis at 45 days are present in fetal epidermis at 45 days (derived from the monocyte-macrophage-histiocyte (derived from the monocyte-macrophage-histiocyte lineage). lineage).

Melanocytes:Melanocytes:50 days.50 days.

Fetal keratinocytes determine the position and number of Fetal keratinocytes determine the position and number of melanocytes within the developing skin.melanocytes within the developing skin.

Langerhans cellsLangerhans cells are monocyte-macrophage- are monocyte-macrophage-histiocyte lineage). histiocyte lineage).

Embryonic…Embryonic…

Dermis Dermis Mesoderm Mesoderm

Four wks: scattered cells.Four wks: scattered cells.

In embryos of 6-14 weeks, three types of cells in the In embryos of 6-14 weeks, three types of cells in the dermis: dermis:

Stellate cellsStellate cells, ,

Phagocytic macrophagesPhagocytic macrophages and and

Granule-secretory cellGranule-secretory cell, either a melanoblast or mast cell. , either a melanoblast or mast cell.

Limited fibrous EC matrix, abundant diffuse matrix Limited fibrous EC matrix, abundant diffuse matrix predominantly of hyaluronic acid.predominantly of hyaluronic acid.


Hyaluronic acid is a highly hydrated molecule that Hyaluronic acid is a highly hydrated molecule that provides a diffuse matrix provides a diffuse matrix cells can freely migrate and cells can freely migrate and proliferate.proliferate.

Fetal skin = 90% water during dvt.Fetal skin = 90% water during dvt.


Types I, II, III, V, and VI collagen are identified.Types I, II, III, V, and VI collagen are identified.

Type I collagenase is present in fetal skin in the periderm, Type I collagenase is present in fetal skin in the periderm, the basal cells, dermal fibroblasts, and dermal matrix, the basal cells, dermal fibroblasts, and dermal matrix,

Role in developmental remodeling during skin Role in developmental remodeling during skin morphogenesis. morphogenesis.


A single plane of vessels and nerves is present in A single plane of vessels and nerves is present in the embryonic dermis, located primarily at the the embryonic dermis, located primarily at the boundary between the dermis and hypodermis.boundary between the dermis and hypodermis.

Mast cells are distributed close to blood vessels, nerves Mast cells are distributed close to blood vessels, nerves and appendages, and are most numerous in the and appendages, and are most numerous in the subpapillary dermis, subpapillary dermis,

Another cell, of bone-marrow origin, may be ancestral to Another cell, of bone-marrow origin, may be ancestral to the histiocyte.the histiocyte.

The Transition of Embryonic to Fetal SkinThe Transition of Embryonic to Fetal SkinThe third month:establishment of adult-like skin pattern. The third month:establishment of adult-like skin pattern. The epidermis stratifies by adding intermediate layer.The epidermis stratifies by adding intermediate layer. Keratin filaments organized to well-developed bundles,Keratin filaments organized to well-developed bundles, An increase in desmosomes. An increase in desmosomes.

Third month…Third month… Intermediate cells express K1 and K10; Intermediate cells express K1 and K10; All of the adult keratins are present in the stratified All of the adult keratins are present in the stratified

fetal epidermis.fetal epidermis. Other markers (antigens, receptors) of keratinocyte Other markers (antigens, receptors) of keratinocyte

differentiation are expressed.differentiation are expressed. Basal cells contain less glycogen Basal cells contain less glycogen maturation and the maturation and the

appearance of primordia of certain epidermal appearance of primordia of certain epidermal appendages.appendages.

Third month…Third month…

As for type I collagenase, a matrix-degrading As for type I collagenase, a matrix-degrading metalloproteinase matrilysin is expressed by basal cells metalloproteinase matrilysin is expressed by basal cells and is concentrated at the early appendage buds and is concentrated at the early appendage buds epidermal-dermal remodeling.epidermal-dermal remodeling.


Most of the dermis is formed by mesenchymal cells Most of the dermis is formed by mesenchymal cells migrating from mesoderm. migrating from mesoderm.

These mesenchymal cells give rise to blood and CT cells: These mesenchymal cells give rise to blood and CT cells: fibroblasts and mast cells of the dermis and the fat fibroblasts and mast cells of the dermis and the fat cells. cells.

The dermis undergoes a transition from a predominantly The dermis undergoes a transition from a predominantly cellular to a fibrous composition. cellular to a fibrous composition.

By the end of the first trimesterBy the end of the first trimester, collagenous connective , collagenous connective tissue is organized in the dermis.tissue is organized in the dermis.

Papillary and reticular regions.Papillary and reticular regions.


The dermis is three to four times the thickness of the The dermis is three to four times the thickness of the epidermis, and remains poorly demarcated from the epidermis, and remains poorly demarcated from the subcutaneous tissue.subcutaneous tissue.

Fibroblasts, macrophages, and mast cells are present. Fibroblasts, macrophages, and mast cells are present.

A second plane of vessels is apparent within the dermis in A second plane of vessels is apparent within the dermis in the position of the subpapillary plexus; the position of the subpapillary plexus;

The basic pattern of adult vasculature is established. The basic pattern of adult vasculature is established.


DEJDEJA continuous lamina densa of the basement membrane A continuous lamina densa of the basement membrane

becomes evident in the second month,becomes evident in the second month,

Hemidesmosomes appear in the third month. Hemidesmosomes appear in the third month.

Nearly all the markers of adult DEJ are expressed by 12 Nearly all the markers of adult DEJ are expressed by 12 weeks EGA.weeks EGA.

Antigens associated with cell-matrix attachment (e.g., Antigens associated with cell-matrix attachment (e.g., pemphigoid, integrins, and laminin) are expressed on pemphigoid, integrins, and laminin) are expressed on the basal keratinocyte, the lamina lucida, the basal keratinocyte, the lamina lucida,

Type VII collagen and anchoring fibrils are evident in the Type VII collagen and anchoring fibrils are evident in the sublamina densa position.sublamina densa position.

APPENDIGES:APPENDIGES:• The earliest development of the hair rudiments occurs The earliest development of the hair rudiments occurs

at about 9 weeks in the regions of the eyebrow, upper at about 9 weeks in the regions of the eyebrow, upper lip and chin. lip and chin.

• The bulk of the remaining follicles begin to develop at The bulk of the remaining follicles begin to develop at approximately 4 to 5 months gestation in a cephalad-approximately 4 to 5 months gestation in a cephalad-to-caudad direction.to-caudad direction.

• The first sign of a hair follicle is a crowding of nuclei in The first sign of a hair follicle is a crowding of nuclei in the basal layer of the epidermis, called the basal layer of the epidermis, called primitive hair primitive hair germ or pregerm stage.germ or pregerm stage.

• The pregerm passes rapidly into the The pregerm passes rapidly into the hair-germ stagehair-germ stage, , the basal cells become high; the nuclei become the basal cells become high; the nuclei become elongated and the structure starts to grow downward elongated and the structure starts to grow downward into the dermis. into the dermis.

• At the same time, mesenchymal cells and fibroblasts At the same time, mesenchymal cells and fibroblasts increase in number to form the rudiment of the hair increase in number to form the rudiment of the hair papilla beneath the hair germpapilla beneath the hair germ the hair peg stage. the hair peg stage.

• At At bulbous hair-peg stagebulbous hair-peg stage, two epithelial swellings , two epithelial swellings appear on the posterior wall of the follicle. appear on the posterior wall of the follicle.

• The lower bulge is where the arrector muscle becomes The lower bulge is where the arrector muscle becomes attached, and the upper is the rudiment of the attached, and the upper is the rudiment of the sebaceous gland.sebaceous gland.

• In many follicles, a third bud later appears above the In many follicles, a third bud later appears above the sebaceous gland; this is the rudiment of the apocrine sebaceous gland; this is the rudiment of the apocrine gland. gland.

• Such rudiments develop in a large number of the Such rudiments develop in a large number of the follicles, including some on the scalp, face, chest, follicles, including some on the scalp, face, chest, abdomen, back and legs, as well as in the axilla, mons abdomen, back and legs, as well as in the axilla, mons pubis, external auditory meatus…pubis, external auditory meatus…

• The hair follicles are arranged in patterns, usually in The hair follicles are arranged in patterns, usually in groups of three. groups of three.

• The first follicles develop over the surface at fixed The first follicles develop over the surface at fixed intervals of between 274 and 350µm. intervals of between 274 and 350µm.

• As the skin grows, these first germs become separated, As the skin grows, these first germs become separated, and new rudiments appear.and new rudiments appear.

• The The matrix keratinocytesmatrix keratinocytes, , located above the located above the basement membrane overlying the follicular papilla, basement membrane overlying the follicular papilla, give rise to the give rise to the hair shafthair shaft & the& the inner root sheath.inner root sheath.

• The melanocytes are dispersed among these matrix The melanocytes are dispersed among these matrix cells. cells.

• As the follicle begins to produce a hair, the central cells As the follicle begins to produce a hair, the central cells of the rudimentary follicle degenerate, forming the path of the rudimentary follicle degenerate, forming the path through which the hair fiber will pass.through which the hair fiber will pass.

Follicular germ stageFollicular germ stagecondensation of mesenchymal cells just beneath the slight condensation of mesenchymal cells just beneath the slight downgrowth or “bud” of fetal basal keratinocytes.downgrowth or “bud” of fetal basal keratinocytes.

Follicular peg stage,Follicular peg stage, organization of keratinocytes in the organization of keratinocytes in the follicle and the mesenchyme of the follicular sheath and follicle and the mesenchyme of the follicular sheath and follicular papilla located at the tip of the follicle.follicular papilla located at the tip of the follicle.

Bulbous hair peg stage,Bulbous hair peg stage,. Two prominent bulge outgrowths . Two prominent bulge outgrowths the uppermost becoms the sebaceous gland and the lowermost is the the uppermost becoms the sebaceous gland and the lowermost is the insertion site of the arrector pili muscle as well as the presumptive insertion site of the arrector pili muscle as well as the presumptive site of the hair follicle stem cells. site of the hair follicle stem cells.

NailsNails• The nail apparatus develops during the ninth embryonic The nail apparatus develops during the ninth embryonic

week from the epidermis of the dorsal tip of the digit as week from the epidermis of the dorsal tip of the digit as a rectangular area, the nail field.a rectangular area, the nail field.

• The proximal border of the nail field extends downward The proximal border of the nail field extends downward and proximally into the dermis to form the nail matrix and proximally into the dermis to form the nail matrix primordium. primordium.

• By the 15By the 15thth week, the nail matrix is completely week, the nail matrix is completely developed and starts to produce the nail plate.developed and starts to produce the nail plate.

Sebaceous glandsSebaceous glands• The sebaceous glands become differentiated at The sebaceous glands become differentiated at

13-15 weeks, and are then large and 13-15 weeks, and are then large and functional. functional.

• These are, at first, solid, hemispherical These are, at first, solid, hemispherical protuberances on the posterior surfaces of the protuberances on the posterior surfaces of the hair pegs. hair pegs.

• The cells contain moderate amounts of The cells contain moderate amounts of glycogen, but soon the cells in the centre lose glycogen, but soon the cells in the centre lose this, and become larger and foamy as they this, and become larger and foamy as they accumulate droplets of lipid.accumulate droplets of lipid.

Eccrine sweat glandsEccrine sweat glands• In embryos of 12 weeks, the rudiments of eccrine In embryos of 12 weeks, the rudiments of eccrine

sweat glands are first identifiable as regularly spaced sweat glands are first identifiable as regularly spaced undulations of the stratum germ. undulations of the stratum germ.

• These start to develop on the palms and soles at about These start to develop on the palms and soles at about 3 months, but not over the rest of the body until the 3 months, but not over the rest of the body until the fifth month. fifth month.

• Cells forming them lie palisading and closely together, Cells forming them lie palisading and closely together, but otherwise they do not differ from the rest of the but otherwise they do not differ from the rest of the stratum germinativum. stratum germinativum.

• By 14-15 weeks, the tips of the eccrine sweat-gland By 14-15 weeks, the tips of the eccrine sweat-gland rudiments have penetrated deeply into the dermis, and rudiments have penetrated deeply into the dermis, and have begun to form the coils.have begun to form the coils.

The Skin of the Second Trimester FetusThe Skin of the Second Trimester Fetus Differentiation and growth are the hallmarks. Differentiation and growth are the hallmarks. The epidermis is still covered by the periderm.The epidermis is still covered by the periderm. The underlying keratinocytes have stratified into layers,The underlying keratinocytes have stratified into layers, By 12-16 weeks(CRL 69-102mm),there are one or more By 12-16 weeks(CRL 69-102mm),there are one or more

intermediate layers. intermediate layers. These cells contain mitochondria, Golgi complexes and These cells contain mitochondria, Golgi complexes and

a few tonofilaments. a few tonofilaments.

Second Trimester…Second Trimester…

skin-differentiation keratins are expressed by cells of skin-differentiation keratins are expressed by cells of

the middle layer. the middle layer. Filaggrin, the protein of the granular layer, is Filaggrin, the protein of the granular layer, is

detectable at 15 weeks.detectable at 15 weeks. From weeks 14 to 21, fibroblasts are numerous and From weeks 14 to 21, fibroblasts are numerous and

active, and active, and Perineurial cells, pericytes, melanoblasts, Merkel cells Perineurial cells, pericytes, melanoblasts, Merkel cells

and mast cells can be identified. and mast cells can be identified.


Merkel cells:Merkel cells:

These appear in the glabrous skin of the fingertips, lip, These appear in the glabrous skin of the fingertips, lip, gingiva and nailbed, and in several other regions, gingiva and nailbed, and in several other regions, around 16 weeks.around 16 weeks.

There are two hypotheses about the embryonic source of There are two hypotheses about the embryonic source of Merkel cells;Merkel cells;

One: they are derived from the neural crest and migrate One: they are derived from the neural crest and migrate into the epidermis along the peripheral nerves. into the epidermis along the peripheral nerves.

The other, for which there is increasing support, assumes The other, for which there is increasing support, assumes that they arise and are derived from epithelial cells.that they arise and are derived from epithelial cells.

Second Trimester…Second Trimester… At 16-18 weeks (CRL 120-150mm) keratinizing cells At 16-18 weeks (CRL 120-150mm) keratinizing cells

from both dorsal and ventral matrices can be from both dorsal and ventral matrices can be distinguished.distinguished.

Cells in the upper intermediate layer synthesizeCells in the upper intermediate layer synthesizefilaggrin and assemble keratohyalin granules, thus filaggrin and assemble keratohyalin granules, thus forming the granular layer. forming the granular layer.

The subjacent intermediate layers then become the The subjacent intermediate layers then become the spinous cells.spinous cells.


By the end of the sixth month the basal, spinous, By the end of the sixth month the basal, spinous, granular, and cornified layers are established. granular, and cornified layers are established.

The first evidence of keratinization:around 22 wk.The first evidence of keratinization:around 22 wk. Keratinization occurs first on the head, face, and palms Keratinization occurs first on the head, face, and palms

and soles.and soles. Once the stratum corneum is formed, the periderm is Once the stratum corneum is formed, the periderm is

sloughed from the epidermal surface into the amniotic sloughed from the epidermal surface into the amniotic fluid. fluid.

Melanocytes transfer pigment to keratinocytes.Melanocytes transfer pigment to keratinocytes.


Portions of the hair follicle, the duct of the sebaceous Portions of the hair follicle, the duct of the sebaceous gland, and the nail keratinize several weeks earlier than gland, and the nail keratinize several weeks earlier than the epidermis (the epidermis (15 to 17 wk). 15 to 17 wk).

Hair follicles become fully mature, and lanugo hairs Hair follicles become fully mature, and lanugo hairs extend from the skin surface in the fifth and sixth extend from the skin surface in the fifth and sixth months.months.


The sebaceous glands secrete sebum that is The sebaceous glands secrete sebum that is released to the skin, combines with dead cells released to the skin, combines with dead cells from within the developing follicle and debris to from within the developing follicle and debris to form the fatty material of the vernix caseosa.form the fatty material of the vernix caseosa.


The eccrine sweat glands are structurally developed in all The eccrine sweat glands are structurally developed in all regions of the body, yet it is unclear if functional. regions of the body, yet it is unclear if functional.

Even at birth only a portion of the glands is functional. Even at birth only a portion of the glands is functional.

The apocrine glands formed well. The apocrine glands formed well.


The dermis increases in thickness during the second The dermis increases in thickness during the second trimester. trimester.

Papillary and reticular regions are further defined in the Papillary and reticular regions are further defined in the fourth month.fourth month.


The hypodermis is recognized as a specific region in the The hypodermis is recognized as a specific region in the fourth month by the organization of connective tissue. fourth month by the organization of connective tissue.

Elastin is synthesized and deposited on the microfibrillar Elastin is synthesized and deposited on the microfibrillar components late in the fifth month.components late in the fifth month.

Cells within the matrix synthesize and store lipid. Cells within the matrix synthesize and store lipid.

By the fifth month a major accumulation ofBy the fifth month a major accumulation ofadipocytes establishes the paniculus adiposus. adipocytes establishes the paniculus adiposus.

Third Trimester of Fetal Skin DevelopmentThird Trimester of Fetal Skin Development Period of finalization of structure & continued growth. Period of finalization of structure & continued growth. All of the adult epidermal layers are present, All of the adult epidermal layers are present, The periderm is gone, The periderm is gone, The epidermal appendages are formed and functional.The epidermal appendages are formed and functional. Active secretion by the glands occurs in the seventh Active secretion by the glands occurs in the seventh

month. month. Thickness of the stratum corneum incr. near birth. Thickness of the stratum corneum incr. near birth.

The adult antigens of the DEJ are expressed, and the The adult antigens of the DEJ are expressed, and the attachment structures are fully formed.attachment structures are fully formed.

The contour of the dermal-epidermal boundary is just The contour of the dermal-epidermal boundary is just beginning to show rete ridges and dermal papillae. beginning to show rete ridges and dermal papillae.

Although the epidermis is equivalent in structure to Although the epidermis is equivalent in structure to adult epidermis, functionally probably is different. adult epidermis, functionally probably is different.

Hormones present at high levels in utero: thyroid Hormones present at high levels in utero: thyroid hormone, glucocorticoids, and estrogens, can hormone, glucocorticoids, and estrogens, can accelerate barrier formation.accelerate barrier formation.

The postnatal functional maturation represents an The postnatal functional maturation represents an adjustment from the fluid environment of the fetus to adjustment from the fluid environment of the fetus to the new air-tissue interface of the newborn. the new air-tissue interface of the newborn.

The thin skin of the premature or newborn infant The thin skin of the premature or newborn infant reflects the relatively thin dermis. reflects the relatively thin dermis.

Elastic fibers are immature in structure, and Elastic fibers are immature in structure, and Matrix continues to accumulate over the first few years Matrix continues to accumulate over the first few years

until the dermis becomes equivalent to that of adult until the dermis becomes equivalent to that of adult skin.skin.

Vasculature?Vasculature? Capillary loops arising from the subpapillary plexus are Capillary loops arising from the subpapillary plexus are

a late formation of the vasculature, and a late formation of the vasculature, and Even at this stage, they are present only in those areas Even at this stage, they are present only in those areas

where there is accentuated dvt.of DEJ (e.g., palms, where there is accentuated dvt.of DEJ (e.g., palms, soles). soles).

They form and are stabilized elsewhere in the body only They form and are stabilized elsewhere in the body only after birth.after birth.

SummarySummary: First tim Sec tim : First tim Sec tim Third tim Third tim

Finally:Stratified,keratinized,squuamFinally:Stratified,keratinized,squuamous epithelium+ Adnexiaous epithelium+ Adnexia

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