Skin-Derived Precursor Cells Promote Wound Healing in Diabetic Mice

Sato, Hideyoshi; Ebisawa, Katsumi; Takanari, Keisuke; Yagi, Shunjiro; Toriyama, Kazuhiro; Yamawaki-Ogata, Aika; Kamei, Yuzuru

doi:10.1097/sap.0000000000000342

Cited by 30 publications

(21 citation statements)

References 33 publications

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“…Model animals frequently used in pre-clinical studies of wound healing are rats and mice. Transgenic mouse models have contributed to the field in terms of specific gene products and their contribution to the wound healing process (185, 186) and by providing disease models (187,188). The translational problem that stems from using rodents is that the biology of the skin and subsequently the wound healing process in rodents is different from human.…”

Section: Modelling Skin and Wound Healingmentioning

confidence: 99%

Applications of human skin in vitro

Lönnqvist¹

2016

Linköping University Medical Dissertations

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Siis älä siitä huoli, näinhän täällä käy Aurinkokin paistaa, vaikkei sitä näy (Eppu Normaali, 1993) So don't you worry about it, that's the way things goThe sun is still shining, even though it doesn't show ABSTRACTChronic wounds are a substantial problem in today's health care and place significant strains on the patient. Successful modelling of the wound healing process is pivotal for the advancement of wound treatment research. Wound healing is a dynamic and multifactorial process involving all constituents of the skin. The progression from haemostasis and inflammation to proliferation of epidermal keratinocytes and dermal fibroblasts, and final scar maturation can be halted and result in a chronic wound that fails to re-epithelialise. The wound healing process constitutes an example of dynamic reciprocity in tissue where cellular changes take place on cues from the extracellular matrix and vice versa when tissue homeostasis is disturbed. The extracellular matrix provides a structural context for the resident cells and the epidermal keratinocytes, and a functioning interplay between the two tissue compartments is crucial for successful wound healing to take place. Work included in this thesis has applied viable human full thickness skin in vitro to investigate the re-epithelialisation process and barrier function of intact skin. The use of full thickness skin in vitro can take into account the contextual aspect of the process where the epidermal keratinocytes are activated and obtain a migratory phenotype, and are continuously dependent on the cues from the extracellular matrix and support of the dermis. When utilising skin for studies on re-epithelialisation, circular standardised full thickness wounds were created and cultured for up to four weeks in tissue culture. In paper I, the organisation of a thick neoepidermis was investigated in the in vitro wound healing model when resident cells were provided with a porous suspended three dimensional gelatin scaffold. In paper II we investigated the use of a fluorescent staining conventionally used for proliferation studies to facilitate the tracing of transplanted epidermal cells in in vitro wounds, in order to improve and expand the use of the model. In paper III the model was utilised to investigate the treatment approach of acidification of wounds to evaluate the suitability of such intervention in regards to keratinocyte function and re-epithelialisation. Studies on reepithelialisation with the aid of the in vitro wound healing model provided insight in neoepidermal structure with porous gelatin scaffolding in the wound, a novel methodological approach to tracing cells and response to constrained wound healing environment. In paper IV, intact human skin was evaluated for modelling the cytotoxic response after exposure to a known irritant compound. To study barrier function, intact skin was exposed to irritants by restricting exposure topically, and full thickness skin in vitro was found suitable for modelling cytotoxicity responses. Employing human full...

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Section: Modelling Skin and Wound Healingmentioning

confidence: 99%

Applications of human skin in vitro

Lönnqvist¹

2016

Linköping University Medical Dissertations

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“…It was also found that transplanted SKPs differentiated into peripheral nerve fibres within the wounds by D28. The authors of the study concluded that wound healing was improved as a result of increased neovascularisation promoted by SKPs (Sato et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated that populations of hair follicle stem cells residing in the bulge, isthmus and infundibulum are able to contribute to wound repair in both the short-and long-term (Ito et al, 2005a;Levy et al, 2007;Plikus et al, 2012). Recent studies have also shown that cells derived from the DP may improve skin wound healing (Sato et al, 2015). In addition, wound re-epithelialisation has been shown to be improved when surrounding hair follicles are in anagen, with a correlation described between the genes upregulated during anagen and those that improve wound healing (Ansell et al, 2011).…”

Section: Introductionmentioning

confidence: 96%

“…Recent evidence suggest that SKPs improve wound closure compared to an acellular control in diabetic mice (Sato et al, 2015). In this study, C57BL/6 mice were treated with either an acellular control, SKPs transduced with a GFP control construct (SKPs+GFP), or…”

Section: Skps Transduced With Constitutively-active Stat5b Acceleratementioning

confidence: 99%

“…shown that DP-derived SKPs improve wound healing and it has been suggested that this occurs due to improved vascularisation of the wound (Sato et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Mesenchymal-epidermal interactions in hair follicle cycling and regeneration

Legrand¹

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The hair follicle is an important skin appendage that arises during development from complex reciprocal signalling between the epidermis and dermis. The multiple epidermal layers of the hair follicle are known to be under the control of the mesenchymal component, the dermal papilla (DP), which has been described as the key regulator of hair follicle induction and maintenance. The hair follicle has elicited interest as a model system for the investigation of tissue and organ regeneration due to its ability to regenerate completely throughout the life of a mammal. This characteristic is attributed to the reservoir of stem cells within the hair follicle, which is modulated by the DP.Although it is known that the DP is central to regulation of the hair follicle, mediators of its signalling are incompletely understood. Potential mediators of DP activity continue to emerge, two of which include the SoxF transcription factor, Sox18, and the transcription factor, STAT5. Sox18 has been implicated in hair type specification by the DP; however, its expression and function remains unclear. STAT5 has been shown in microarray analyses of the DP to be specifically expressed and upregulated, while studies involving STAT5 genetic knockouts display a hair phenotype. More recently, STAT5 has been implicated in autoimmune conditions affecting the hair follicle such as alopecia areata.To investigate further the role of STAT5 in the DP, I have hypothesised that STAT5 plays a key role in the DP's hair follicle inductive properties and regulation of cycling.STAT5 activation in the DP was characterised through immunofluorescence staining of mouse back skin at various stages of hair follicle development and cycling. Back skin was obtained from Topflash transgenic mice, a canonical Wnt reporter transgenic mouse driving luciferase expression, using β-catenin activity to monitor hair cycling via live bioluminescence imaging. While embryonic skin did not display any activation of STAT5, during postnatal hair follicle development (P0-P19), the majority of phospho-STAT5 positive DP were present within telogen phase, to a lesser extent within catagen and not at all during anagen. Adult skin showed phospho-STAT5 activation beginning in late catagen and persisting through to early anagen.Characterisation of SOCS2 by immunofluorescence, a downstream STAT5 transcriptional target, showed expression corresponding to the chronology of phospho-STAT5 activity.Hair regeneration assays were performed with DP cells using SKP culture with STAT5 activity modified through adenovirus constructs. SKPs derived from C57BL/6 neonates and STAT5 lox/lox neonates were transduced with STAT5A/B constitutively-active and crerecombinase constructs, respectively. These transduced SKPs were then used in patch assay experiments and DP formation was quantified using a green fluorescent protein ii (GFP) reporter. SKPs transduced with constitutively-active STAT5 were significantly better at forming hair follicle DP than control SKPs transduced with GFP alone. SKPs with...

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A Cooperative Copper Metal–Organic Framework‐Hydrogel System Improves Wound Healing in Diabetes

Xiao

Chen

et al. 2016

Adv Funct Materials

325

247

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Chronic non-healing wounds remain a major clinical challenge that would benefit from the development of advanced, regenerative dressings that promote wound closure within a clinically relevant time frame. The use of copper ions has shown promise in wound healing applications possibly by promoting angiogenesis. However, reported treatments that use copper ions require multiple applications of copper salts or oxides to the wound bed, exposing the patient to potentially toxic levels of copper ions and resulting in variable outcomes. Herein we set out to assess whether copper metal organic framework nanoparticles (HKUST-1 NPs) embedded within an antioxidant thermoresponsive citrate-based hydrogel would decrease copper ion toxicity and accelerate wound healing in diabetic mice. HKUST-1 and poly-(polyethyleneglycol citrate-co-N-isopropylacrylamide) (PPCN) were synthesized and characterized. HKUST-1 NP stability in a protein solution with and without embedding them in PPCN hydrogel was determined. Copper ion release, cytotoxicity, apoptosis, and in vitro migration processes were measured. Wound closure rates and wound blood perfusion were assessed in vivo using the splinted excisional dermal wound diabetic mouse model. HKUST-1 NP disintegrated in protein solution while HKUST-1 NPs embedded in PPCN (H-HKUST-1) were protected from degradation and copper ions were slowly released. Cytotoxicity and apoptosis due to copper ion release were significantly reduced while dermal cell migration in vitro and wound closure rates in vivo were significantly enhanced. In vivo, H-HKUST-1 induced angiogenesis, collagen deposition, and re-epithelialization during wound healing in diabetic mice. These results suggest that a cooperatively stabilized, copper ion-releasing H-HKUST-1 hydrogel is a promising innovative dressing for the treatment of chronic wounds.

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Skin-Derived Precursor Cells Promote Wound Healing in Diabetic Mice

Abstract: Skin-derived precursor cells promoted diabetic wound healings through vasculogenesis at the early stage of wound healing. Skin-derived precursor cells are a possible therapeutic tool for diabetic impaired wound healing.

Cited by 30 publications

References 33 publications

Applications of human skin in vitro

Applications of human skin in vitro

Mesenchymal-epidermal interactions in hair follicle cycling and regeneration

A Cooperative Copper Metal–Organic Framework‐Hydrogel System Improves Wound Healing in Diabetes

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