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Tissue Engineering. Part C, Methods Jul 2021Reconstructed human skin models are a valuable tool for drug discovery, disease modeling, and basic research. In the past decades, major progress has been made in this...
Reconstructed human skin models are a valuable tool for drug discovery, disease modeling, and basic research. In the past decades, major progress has been made in this field leading to the development of full-thickness skin models (FTSms) better representative of the native human skin by including the cellular cross talk between the dermal and epidermal layers. However, current available FTSms still present important limitations since they are only suitable for short-term studies, include nonhuman extracellular matrix (ECM) components and have a weak skin barrier function compared with human skin. In this study, a fibroblast-derived matrix was combined with the use of an inert polystyrene scaffold for the development of a fully human dermis capable of supporting a differentiated epidermis. To produce a pigmented FTSm, a coculture with keratinocytes, melanocytes, and fibroblasts was established. The structure and functionality of the developed FTSms were studied for short- and long-term cultivation using histological and immunofluorescence staining. The integrity of the skin barrier was evaluated using transepithelial electrical resistance (TEER) measurements. It was possible to obtain a mature dermis capable of supporting an epidermis without keratinocyte infiltration in only 6 days. ECM components (collagen IV and fibrin) were secreted by the fibroblasts and accumulated in the scaffold structure, recreating the microenvironment of the native human dermis. Moreover, the use of a scaffold resulted in a structure with mechanical stability due to its noncontracting nature. The coculture of primary human keratinocytes resulted in a terminally differentiated skin equivalent that could maintain its architecture and homeostasis up to 50 days. Melanocytes were correctly integrated within the epidermal basal layer and made it possible to reproduce constitutive pigmentation. TEER levels increased during culture time, reaching values of 1.1 ± 0.2 kΩ.cm for the FTSm, indicative of a functional skin barrier.
Topics: Dermis; Epidermal Cells; Fibroblasts; Humans; Keratinocytes; Skin
PubMed: 34148380
DOI: 10.1089/ten.TEC.2021.0069 -
International Journal of Molecular... Jan 2020Scarring and regeneration are two physiologically opposite endpoints to skin injuries, with mammals, including humans, typically healing wounds with fibrotic scars. We... (Review)
Review
Scarring and regeneration are two physiologically opposite endpoints to skin injuries, with mammals, including humans, typically healing wounds with fibrotic scars. We aim to provide an updated review on fibroblast heterogeneity as determinants of the scarring-regeneration continuum. We discuss fibroblast-centric mechanisms that dictate scarring-regeneration continua with a focus on intercellular and cell-matrix adhesion. Improved understanding of fibroblast lineage-specific mechanisms and how they determine scar severity will ultimately allow for the development of antiscarring therapies and the promotion of tissue regeneration.
Topics: Animals; Cicatrix; Dermis; Fibroblasts; Humans; Regeneration; Skin; Wound Healing
PubMed: 31963533
DOI: 10.3390/ijms21020617 -
The Journal of Investigative Dermatology Sep 2022Clinical application of mechanical stretching is a reconstructive method for skin repair. Although studies have reported dermal fibroblast heterogeneity, whether...
Clinical application of mechanical stretching is a reconstructive method for skin repair. Although studies have reported dermal fibroblast heterogeneity, whether stretching affects individual fibroblast subpopulations equally remains unclear. In this study, we show the changes in dermal structure and papillary fibroblast (Fp) in regenerated human skin. Exhausted skin regeneration caused dermal‒epidermal junction flattening, papillary dermis thinning, and an increase in type III collagen-to-type I collagen ratio, with upregulated hallmarks of aging. Well-regenerated skin displayed a notable increase in the Fp population. Consistent changes were observed in the rat expansion model. Moreover, we found that TGFβ1 expression was especially increased in skin showing good regeneration. Activation of the TGFβ1/SMAD2/3 pathway improved exhausted skin regeneration and resulted in increased collagen content and Fp proliferation, whereas pharmacological inhibition of TGFβ1 action impacted well-regenerated skin. Short-term mechanical stretching that promoted skin regeneration enhanced Fp proliferation, extracellular matrix synthesis, and increased TGFβ1 expression, leading to good regeneration. Conversely, long-term stretching induced premature Fp senescence, leading to poor regeneration. This work shows the mechanism of mechanical stretching in well-skin regeneration that enhances Fp proliferation and extracellular matrix synthesis through the TGFβ1/SMAD2/3 pathway and highlights a crucial role of Fps in stretching-induced skin regeneration.
Topics: Animals; Dermis; Extracellular Matrix; Fibroblasts; Humans; Rats; Regeneration; Skin
PubMed: 35181299
DOI: 10.1016/j.jid.2021.11.043 -
Nature Communications Mar 2015Tear resistance is of vital importance in the various functions of skin, especially protection from predatorial attack. Here, we mechanistically quantify the extreme...
Tear resistance is of vital importance in the various functions of skin, especially protection from predatorial attack. Here, we mechanistically quantify the extreme tear resistance of skin and identify the underlying structural features, which lead to its sophisticated failure mechanisms. We explain why it is virtually impossible to propagate a tear in rabbit skin, chosen as a model material for the dermis of vertebrates. We express the deformation in terms of four mechanisms of collagen fibril activity in skin under tensile loading that virtually eliminate the possibility of tearing in pre-notched samples: fibril straightening, fibril reorientation towards the tensile direction, elastic stretching and interfibrillar sliding, all of which contribute to the redistribution of the stresses at the notch tip.
Topics: Animals; Biomechanical Phenomena; Dermis; Elasticity; Fibrillar Collagens; Microscopy, Electron, Scanning; Rabbits; Skin; Stress, Mechanical; Tensile Strength
PubMed: 25812485
DOI: 10.1038/ncomms7649 -
Proceedings of the National Academy of... Jan 2015There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic...
There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic patients. A major factor underlying this is reduced neovascularization caused by impaired activity of the transcription factor hypoxia inducible factor-1 alpha (HIF-1α). In diabetes, HIF-1α function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1α transactivation. We examined whether local enhancement of HIF-1α activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1α activity we designed a transdermal drug delivery system (TDDS) containing the FDA-approved small molecule deferoxamine (DFO), an iron chelator that increases HIF-1α transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. Applying this TDDS to a pressure-induced ulcer model in diabetic mice, we found that transdermal delivery of DFO significantly improved wound healing. Unexpectedly, prophylactic application of this transdermal delivery system also prevented diabetic ulcer formation. DFO-treated wounds demonstrated increased collagen density, improved neovascularization, and reduction of free radical formation, leading to decreased cell death. These findings suggest that transdermal delivery of DFO provides a targeted means to both prevent ulcer formation and accelerate diabetic wound healing with the potential for rapid clinical translation.
Topics: Administration, Cutaneous; Animals; Apoptosis; Deferoxamine; Dermis; Diabetes Complications; Diabetes Mellitus, Experimental; Drug Delivery Systems; Mice, Inbred C57BL; Necrosis; Neovascularization, Physiologic; Pressure; Reactive Oxygen Species; Stress, Physiological; Ulcer; Vascular Endothelial Growth Factor A; Wound Healing
PubMed: 25535360
DOI: 10.1073/pnas.1413445112 -
Anais Brasileiros de Dermatologia 2016Scleromyxedema or lichen myxedematosus is a rare papular mucinosis of chronic and progressive course and unknown etiology. It is commonly associated with monoclonal...
Scleromyxedema or lichen myxedematosus is a rare papular mucinosis of chronic and progressive course and unknown etiology. It is commonly associated with monoclonal gammopathy and may show extracutaneous manifestations, affecting the heart, lung, kidney, and nerves. The diagnosis is based on four criteria: generalized papular and sclerodermoid lesions; mucin deposition, fibroblast proliferation, and fibrosis in the histopathology; monoclonal gammopathy; and no thyroid disorders. This article reports the case of a scleromyxedema patient with a recent history of acute myocardial infarction and monoclonal gammopathy.
Topics: Cell Proliferation; Dermis; Fibroblasts; Humans; Male; Middle Aged; Mucins; Scleromyxedema
PubMed: 28099617
DOI: 10.1590/abd1806-4841.20165725 -
Oncotarget Apr 2017To explore the profibrotic characteristics of the autografted dermis, acellular dermal matrix, and dermal fibroblasts from superficial/deep layers of pig skin, 93 wounds...
To explore the profibrotic characteristics of the autografted dermis, acellular dermal matrix, and dermal fibroblasts from superficial/deep layers of pig skin, 93 wounds were established on the dorsa of 7 pigs. 72 wounds autografted with the superficial/deep dermis and acellular dermal matrix served as the superficial/deep dermis and acellular dermal matrix group, respectively, and were sampled at 2, 4, and 8 weeks post-wounding. 21 wounds autografted with/without superficial/deep dermal fibroblasts served as the superficial/deep dermal fibroblast group and the control group, respectively, and were sampled at 2 weeks post-wounding. The hematoxylin and eosin staining showed that the wounded skin thicknesses in the deep dermis group (superficial acellular dermal matrix group) were significantly greater than those in the superficial dermis group (deep acellular dermal matrix group) at each time point, the thickness of the cutting plane in the deep dermal fibroblast group was significantly greater than that in the superficial dermal fibroblast group and the control group. The western blots showed that the α-smooth muscle actin expression in the deep dermis group (superficial acellular dermal matrix group) was significantly greater than that in the superficial dermis group (deep acellular dermal matrix group) at each time point. In summary, the deep dermis and dermal fibroblasts exhibited more profibrotic characteristics than the superficial ones, on the contrary, the deep acellular dermal matrix exhibited less profibrotic characteristics than the superficial one.
Topics: Acellular Dermis; Actins; Animals; Blotting, Western; Cells, Cultured; Cicatrix, Hypertrophic; Dermis; Disease Models, Animal; Female; Fibroblasts; Fibrosis; Humans; Muscle, Smooth; Skin; Skin Transplantation; Swine; Time Factors; Transplantation, Autologous; Wound Healing
PubMed: 28423561
DOI: 10.18632/oncotarget.15389 -
International Wound Journal Apr 2024Keloid are a fibroproliferative disorder caused by abnormal healing of skin, specifically reticular dermis, when subjected to pathological or inflammatory scars... (Review)
Review
Keloid are a fibroproliferative disorder caused by abnormal healing of skin, specifically reticular dermis, when subjected to pathological or inflammatory scars demonstrating redness, elevation above the skin surface, extension beyond the original wound margins and resulting in an unappealing cosmetic appearance. The severity of keloids and risk of developing keloids scars are subjected to elevation by other contributing factors such as systemic diseases, general health conditions, genetic disorders, lifestyle and natural environment. In particular, recently, daily physical work interpreted into mechanical force as well as the interplay between mechanical factors such as stress, strain and stiffness have been reported to strongly modulate the cellular behaviour of keloid formation, affect their location and shape in keloids. Herein, we review the extensive literature on the effects of these factors on keloids and the contributing predisposing mechanisms. Early understanding of these participating factors and their effects in developing keloids may raise the patient awareness in preventing keloids incidence and controlling its severity. Moreover, further studies into their association with keloids as well as considering strategies to control such factors may help clinicians to prevent keloids and widen the therapeutic options.
Topics: Humans; Keloid; Cicatrix, Hypertrophic; Skin; Dermis; Life Style
PubMed: 38584345
DOI: 10.1111/iwj.14865 -
Anais Brasileiros de Dermatologia 2018
Topics: Adult; Biopsy; Brazil; Cities; Dermis; Erythema; Female; Geography, Medical; Humans; Leishmaniasis, Cutaneous; Male; Urban Population; Young Adult
PubMed: 29641726
DOI: 10.1590/abd1806-4841.20186713 -
JCI Insight Jun 2021Dietary sodium intake mismatches urinary sodium excretion over prolonged periods. Our aims were to localize and quantify electrostatically bound sodium within human skin...
BACKGROUND
Dietary sodium intake mismatches urinary sodium excretion over prolonged periods. Our aims were to localize and quantify electrostatically bound sodium within human skin using triple-quantum-filtered (TQF) protocols for MRI and magnetic resonance spectroscopy (MRS) and to explore dermal sodium in type 2 diabetes mellitus (T2D).
METHODS
We recruited adult participants with T2D (n = 9) and euglycemic participants with no history of diabetes mellitus (n = 8). All had undergone lower limb amputations or abdominal skin reduction surgery for clinical purposes. We used 20 μm in-plane resolution 1H MRI to visualize anatomical skin regions ex vivo from skin biopsies taken intraoperatively, 23Na TQF MRI/MRS to explore distribution and quantification of freely dissolved and bound sodium, and inductively coupled plasma mass spectrometry to quantify sodium in selected skin samples.
RESULTS
Human dermis has a preponderance (>90%) of bound sodium that colocalizes with the glycosaminoglycan (GAG) scaffold. Bound and free sodium have similar anatomical locations. T2D associates with a severely reduced dermal bound sodium capacity.
CONCLUSION
We provide the first evidence to our knowledge for high levels of bound sodium within human dermis, colocating to the GAG scaffold, consistent with a dermal "third space repository" for sodium. T2D associates with diminished dermal electrostatic binding capacity for sodium.
Topics: Adult; Aged; Dermis; Diabetes Mellitus, Type 2; Female; Glycosaminoglycans; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Sodium
PubMed: 34003801
DOI: 10.1172/jci.insight.145470