Fibroblast heterogeneity and its implications for engineering organotypic skin models in vitro

Sriram, Gopu; Bigliardi, Paul L.; Bigliardi-Qi, Mei

doi:10.1016/j.ejcb.2015.08.001

Cited by 210 publications

(210 citation statements)

References 360 publications

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“…The dermal layer is rich in collagens (I, III, IV, VII), fibronectin and glycosaminoglycans. Dermis is also organized into an upper 'papillary' (high ratio of collagen type III to type I) and a lower 'reticular' (low ratio of collagen type III to type I) region [187]. At the epidermal-dermal junction, a basement membrane mostly composed of laminin and collagen IV provides a physical barrier between two layers [15].…”

Section: Requirements Of Printed Skinmentioning

confidence: 99%

Advances in bioprinted cell-laden hydrogels for skin tissue engineering

et al. 2017

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Bioprinting technologies are powerful additive biofabrication techniques to produce cellular constructs for skin tissue engineering owing to their unique ability to precisely pattern living and non-living materials in predefined spatial locations. This unique feature, combined with the computer controlled printing and medical imaging techniques, enable researchers and clinicians to generate patient specific constructs partly replicating the intricate compositional and architectural organization of the skin. Bioprinting has been used to automatically dispense hydrogels with skin cells located in prescribed sites that promote skin formation in vitro and in vivo. Current skin bioprinting approaches mostly rely on the sequential printing of fibroblasts and keratinocytes embedded within a homogeneous hydrogel. Although such approaches have already been translated to pre-clinical scenarios, they still present limitations in terms of fully replicating the cellular and extracellular matrix (ECM) heterogeneity in native skin. The success of bioprinting for skin repair strongly depends on the design of printable bioinks capable of supporting the function of printed cells and stimulating the production of new ECM components. To better mimic the human skin, novel developments in dedicated bioprinting technologies, in the design of bioinks, as well as in the printing of vascularised constructs are necessary. This paper presents an overview regarding the use of bioprinting for skin tissue engineering applications. The operating principles of bioprinting technologies are outlined along with requirements of printed skin constructs. Finally, preclinical results are summarized and future perspectives for the field are highlighted.

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Section: Requirements Of Printed Skinmentioning

confidence: 99%

Advances in bioprinted cell-laden hydrogels for skin tissue engineering

et al. 2017

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“…Fibroblasts in di erent parts of the body arise from di erent embryonic origins; broblasts in the face and neck regions originate from the neural crest, while dorsal skin originates from the dermato-myotome and ventral skin comes from the lateral plate mesoderm (Sriram et al, 2015). Two populations of mouse embryonic broblasts can be distinguished by their expression (or not) of Engrailed 1 (Rinkevich et al, 2015).…”

Section: Pericytesmentioning

confidence: 99%

Fibroblast Differentiation and Models of Human Skin

Rakar¹

2016

Linköping University Medical Dissertations

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Denna bok avhandlar en riktning av biomedicinsk forskning som i det långa loppet sy ar till att nå bättre och banbrytande sätt att läka våra kroppar. Forskningen vilar på en tredelad grund -viktiga kunskaper som leder mot en generell förståelse för hur celler blir till vävnader, hur vävnad-er och organ kan manipuleras på ett kliniskt användbart sätt, och till sist hur denna kunskap kan appliceras på människans hudorgan.Den första delen handlar om cellers identitet, och den stora potentialen som våra egna stamceller har för framtidens läkekonst. Genom att förstå hur celler egentligen fungerar på arvsmassenivå kan vi utöka arsenalen av verktyg vi har för att få celler att bete sig på de sätt som behövs för att skapa nya organ. Vi har jobbat med att karakterisera och manipulera broblaster, en av de vanligaste celltyperna i människokroppen, och bland annat tagit fram olika typer av fettceller.Den andra delen handlar om hur man använder celler, biokemiska faktorer och biokompatibla material för att konstruera vävnader och organ. Innan forskningen når klinisk användbarhet har vi möjlighet att bygga begränsade modellsystem för att studera människans biologi. Cellsystem på labbet är mycket viktiga verktyg för att föra forskningen på vävnadsbyg-gande framåt.Den tredje delen behandlar hudforskning speci kt, och här samlas kunskaper från tidigare delarna som är relevanta för mänsklig hud. Här beskrivs användningen av två olika hudmodeller för att undersöka proceser viktiga vid sårläkning. Vidare beskrivs planerna kring ett större påbörjat projekt som sy ar till att använda alla tidigare lärdomar och tekniker för att åstadkomma en ny terapi för sårläkning.Abstract is thesis combines three publications and one manuscript, covering two principal topics: functional di erentiation of human broblasts and, laboratory models of human skin. e two topics favourably unite in the realm of tissue engineering. is thesis is therefore split into three main parts: 1. a discussion of phenotypic plasticity as it pertains to broblasts and the stem cell continuum; 2. a short review of engineered tissue, with particular focus on soluble factors and materials; and, 3. a motivated review of the biology, diversity and culture of skin, including skin construction. e intended goal of our research endeavor was to achieve the formulation of a bioactive therapy for skin regeneration. e main hypothesis was that broblast-to-keratinocyte di erentiation would facilitate wound healing, and that the protocol for such a method could be adapted to clinical translation. e foundation for the hypothesis lay in the di erentiation capabilities of primary dermal broblasts (Paper I). However, the goal has not yet been achieved. Instead, intermediate work on the construction of skin for the purpose of creating a model test-bed has resulted in two other publications. e use of excised human skin, a formidable reference sample for tissue engineered skin, has been used to investigate a gelatin-based material in re-epithelialization (Paper II). A rst attempt at standardizi...

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“…The inductive and maintenance growth factors produced by sitespecific and appendage-specific skin fibroblasts are just starting to be defined (Driskell et al, 2013;Driskell and Watt, 2015;Sriram et al, 2015). Perhaps, the most well-studied cells in this respect are the dermal papilla fibroblasts of the hair follicle, which induce both the formation (Jahoda et al, 1984(Jahoda et al, , 1993Plikus, 2014;Yang and Cotsarelis, 2010) and regenerative cycling of hair follicles (Chi et al, 2013;Clavel et al, 2012;Enshell-Seijffers et al, 2010;Morgan, 2014;Rendl et al, 2005;Sennett and Rendl, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Dermal papilla fibroblast-specific factors include the fibroblast growth factors Fgf7 and Fgf10 (Chi et al, 2013;Clavel et al, 2012;Enshell-Seijffers et al, 2010;Morgan, 2014;Rendl et al, 2005;Sennett and Rendl, 2012), bone morphogenetic proteins Bmp4 and Bmp6 (Clavel et al, 2012;Rendl et al, 2005Rendl et al, , 2008, the BMP antagonist noggin (Botchkarev et al, 1999(Botchkarev et al, , 2002Rendl et al, 2005), transforming growth factor TGFβ2 (Oshimori and Fuchs, 2012) and many others (Morgan, 2014;Rendl et al, 2005;Sennett and Rendl, 2012). Outside of the hair follicle, skin fibroblasts also feature significant specialization and heterogeneity; however, our understanding of their molecular profiles is still rudimentary (Driskell et al, 2013;Driskell and Watt, 2015;Sriram et al, 2015). For instance, recent studies show that papillary (upper) dermis fibroblasts express higher levels of growth factors that control epidermal proliferation and differentiation, whereas those from the reticular (lower) dermis produce high levels of signaling molecules associated with matrix production (Driskell et al, 2013;Driskell and Watt, 2015;Sriram et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Outside of the hair follicle, skin fibroblasts also feature significant specialization and heterogeneity; however, our understanding of their molecular profiles is still rudimentary (Driskell et al, 2013;Driskell and Watt, 2015;Sriram et al, 2015). For instance, recent studies show that papillary (upper) dermis fibroblasts express higher levels of growth factors that control epidermal proliferation and differentiation, whereas those from the reticular (lower) dermis produce high levels of signaling molecules associated with matrix production (Driskell et al, 2013;Driskell and Watt, 2015;Sriram et al, 2015). These findings imply that transcriptional heterogeneity is an intrinsic property related to the developmental history of specific fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

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Estrogen modulates mesenchyme-epidermis interactions in the adult nipple

Spandau

et al. 2017

Development

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Maintenance of specialized epidermis requires signals from the underlying mesenchyme; however, the specific pathways involved remain to be identified. By recombining cells from the ventral skin of the K14-PTHrP transgenic mice [which overexpress parathyroid hormone-related protein (PTHrP) in their developing epidermis and mammary glands] with those from wild type, we show that transgenic stroma is sufficient to reprogram wild-type keratinocytes into nipplelike epidermis. To identify candidate nipple-specific signaling factors, we compared gene expression signatures of sorted Pdgfrα-positive ventral K14-PTHrP and wild-type fibroblasts, identifying differentially expressed transcripts that are involved in WNT, HGF, TGFβ, IGF, BMP, FGF and estrogen signaling. Considering that some of the growth factor pathways are targets for estrogen regulation, we examined the upstream role of this hormone in maintaining the nipple. Ablation of estrogen signaling through ovariectomy produced nipples with abnormally thin epidermis, and we identified TGFβ as a negatively regulated target of estrogen signaling. Estrogen treatment represses Tgfβ1 at the transcript and protein levels in K14-PTHrP fibroblasts in vitro, while ovariectomy increases Tgfb1 levels in K14-PTHrP ventral skin. Moreover, ectopic delivery of Tgfβ1 protein into nipple connective tissue reduced epidermal proliferation. Taken together, these results show that specialized nipple epidermis is maintained by estrogen-induced repression of TGFβ signaling in the local fibroblasts.

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Fibroblast heterogeneity and its implications for engineering organotypic skin models in vitro

Cited by 210 publications

References 360 publications

Advances in bioprinted cell-laden hydrogels for skin tissue engineering

Advances in bioprinted cell-laden hydrogels for skin tissue engineering

Fibroblast Differentiation and Models of Human Skin

Estrogen modulates mesenchyme-epidermis interactions in the adult nipple

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