Establishment of a complex skin structure via layered co-culture of keratinocytes and fibroblasts derived from induced pluripotent stem cells

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Abstract

Background

Skin is an organ that plays an important role as a physical barrier and has many other complex functions. Skin mimetics may be useful for studying the pathophysiology of diseases in vitro and for repairing lesions in vivo. Cord blood mononuclear cells (CBMCs) have emerged as a potential cell source for regenerative medicine. Human induced pluripotent stem cells (iPSCs) derived from CBMCs have great potential for allogenic regenerative medicine. Further study is needed on skin differentiation using CBMC-iPSCs.

Methods

Human iPSCs were generated from CBMCs by Sendai virus. CBMC-iPSCs were differentiated to fibroblasts and keratinocytes using embryonic body formation. To generate CBMC-iPSC-derived 3D skin organoid, CBMC-iPSC-derived fibroblasts were added into the insert of a Transwell plate and CBMC-iPSC-derived keratinocytes were seeded onto the fibroblast layer. Transplantation of 3D skin organoid was performed by the tie-over dressing method.

Results

Epidermal and dermal layers were developed using keratinocytes and fibroblasts differentiated from cord blood-derived human iPSCs, respectively. A complex 3D skin organoid was generated by overlaying the epidermal layer onto the dermal layer. A humanized skin model was generated by transplanting this human skin organoid into SCID mice and effectively healed skin lesions.

Conclusions

This study reveals that a human skin organoid generated using CBMC iPSCs is a novel tool for in-vitro and in-vivo dermatologic research.

Electronic supplementary material

The online version of this article (10.1186/s13287-018-0958-2) contains supplementary material, which is available to authorized users.

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Most cited references 47

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TGF-β signaling in fibrosis.

Anna Biernacka, Marcin Dobaczewski, Nikolaos G Frangogiannis (2011)

Transforming growth factor β (TGF-β) is a central mediator of fibrogenesis. TGF-β is upregulated and activated in fibrotic diseases and modulates fibroblast phenotype and function, inducing myofibroblast transdifferentiation while promoting matrix preservation. Studies in a wide range of experimental models have demonstrated the involvement of the canonical activin receptor-like kinase 5/Smad3 pathway in fibrosis. Smad-independent pathways may regulate Smad activation and, under certain conditions, may directly transduce fibrogenic signals. The profibrotic actions of TGF-β are mediated, at least in part, through induction of its downstream effector, connective tissue growth factor. In light of its essential role in the pathogenesis of fibrosis, TGF-β has emerged as an attractive therapeutic target. However, the pleiotropic and multifunctional effects of TGF-β and its role in tissue homeostasis, immunity and cell proliferation raise concerns regarding potential side effects that may be caused by TGF-β blockade. This minireview summarizes the role of TGF-β signaling pathways in the fibrotic response.

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Induced pluripotent stem cells: past, present, and future.

Shinya Yamanaka (2012)

The development of iPSCs reflected the merging of three major scientific streams and has in turn led to additional new branches of investigation. However, there is still debate about whether iPSCs are functionally equivalent to ESCs. This question should be answered only by science, not by politics or business. Copyright © 2012 Elsevier Inc. All rights reserved.

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Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials

Paul Noble, Carlo Albera, Williamson Bradford … (2016)

Pirfenidone is an antifibrotic agent that has been evaluated in three multinational phase 3 trials in patients with idiopathic pulmonary fibrosis (IPF). We analysed pooled data from the multinational trials to obtain the most precise estimates of the magnitude of treatment effect on measures of disease progression. All patients randomised to pirfenidone 2403 mg·day−1 or placebo in the CAPACITY or ASCEND studies were included in the analysis. Pooled analyses of outcomes at 1 year were based on the pre-specified end-points and analytic methods described in the ASCEND study protocol. A total of 1247 patients were included in the analysis. At 1 year, pirfenidone reduced the proportion of patients with a ≥10% decline in per cent predicted forced vital capacity or death by 43.8% (95% CI 29.3–55.4%) and increased the proportion of patients with no decline by 59.3% (95% CI 29.0–96.8%). A treatment benefit was also observed for progression-free survival, 6-min walk distance and dyspnoea. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group, but rarely led to discontinuation. Analysis of data from three phase 3 trials demonstrated that treatment with pirfenidone for 1 year resulted in clinically meaningful reductions in disease progression in patients with IPF.

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Author and article information

Contributors

Yena Kim: kyena0430@gmail.com

Narae Park: narae5322@gmail.com

Yeri Alice Rim: llyerill0114@gmail.com

Yoojun Nam: givingtreemax@gmail.com

Hyerin Jung: ilovehyelin@gmail.com

Kijun Lee: bluebusker@gmail.com

Ji Hyeon Ju: 82-2-2258-6893 , juji@catholic.ac.kr

Journal

Journal ID (nlm-ta): Stem Cell Res Ther

Journal ID (iso-abbrev): Stem Cell Res Ther

Title: Stem Cell Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-6512

Publication date (Electronic): 13 August 2018

Publication date PMC-release: 13 August 2018

Publication date Collection: 2018

Volume: 9

Electronic Location Identifier: 217

Affiliations

[1 ]ISNI 0000 0004 0470 4224, GRID grid.411947.e, CiSTEM laboratory, Catholic iPSC Research Center, College of Medicine, , The Catholic University of Korea, ; 505 Banpo-dong, Seocho-gu, Seoul, 137-701 Republic of Korea

[2 ]ISNI 0000 0004 0470 4224, GRID grid.411947.e, Division of Rheumatology, Department of Internal Medicine, College of Medicine, , Seoul St. Mary’s Hospital, The Catholic University of Korea, ; 505 Banpo-dong, Seocho-gu, Seoul, 137-701 Republic of Korea

Article

Publisher ID: 958

DOI: 10.1186/s13287-018-0958-2

PMC ID: 6090613

PubMed ID: 30103800

SO-VID: c0d03d97-4d75-4516-88cd-b20e24f8c5e7

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 2 April 2018

Date revision received : 10 July 2018

Date accepted : 16 July 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100003625, Ministry of Health and Welfare;

Award ID: HI16C2177

Award Recipient : Ji Hyeon Ju

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: cord blood mononuclear cell,induced pluripotent stem cells,fibroblast,keratinocyte,3d skin organoid

Data availability:

ScienceOpen disciplines: Molecular medicine

Keywords: cord blood mononuclear cell, induced pluripotent stem cells, fibroblast, keratinocyte, 3d skin organoid

Establishment of a complex skin structure via layered co-culture of keratinocytes and fibroblasts derived from induced pluripotent stem cells

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

Related collections

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Most cited references 47

TGF-β signaling in fibrosis.

Induced pluripotent stem cells: past, present, and future.

Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials

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