Generation of 3D Skin Equivalents Fully Reconstituted from Human Induced Pluripotent Stem Cells (iPSCs)
Open accessAbstract
Recent generation of patient-specific induced pluripotent stem cells (PS-iPSCs) provides significant advantages for cell- and gene-based therapy. Establishment of iPSC-based therapy for skin diseases requires efficient methodology for differentiating iPSCs into both keratinocytes and fibroblasts, the major cellular components of the skin, as well as the reconstruction of skin structures using these iPSC-derived skin components. We previously reported generation of keratinocytes from human iPSCs for use in the treatment of recessive dystrophic epidermolysis bullosa (RDEB) caused by mutations in the COL7A1 gene. Here, we developed a protocol for differentiating iPSCs into dermal fibroblasts, which also produce type VII collagen and therefore also have the potential to treat RDEB. Moreover, we generated in vitro 3D skin equivalents composed exclusively human iPSC-derived keratinocytes and fibroblasts for disease models and regenerative therapies for skin diseases, first demonstrating that iPSCs can provide the basis for modeling a human organ derived entirely from two different types of iPSC-derived cells.
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Human skin equivalents have notable drawbacks, such as a lack of crucial skin tissue structures (e.g., hair follicles and sebaceous glands) and limited culture durations (e.g., 2-3 weeks).
“However, human skin equivalents have notable drawbacks, such as a lack of crucial skin tissue structures (e.g., hair follicles and sebaceous glands) and limited culture durations (e.g., 2–3 weeks)”
From Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells (2022) · cites this paper as [19]
The Discussion describes the paper’s in vitro 3D skin equivalent as lacking skin appendages, supporting the structural drawback. The Methods report harvesting the equivalent after approximately 18–20 days of preparation, but do not say that its culture duration is limited to 2–3 weeks. (LLM, conf=0.86)
Experimental — accuracy not yet measuredConventional primary cell-based HSEs have transitioned to more standardized and reproducible in vitro culture models using immortalized cell lines or hiPSC-derived cells.
“Furthermore, in response to challenges associated with donor variability, conventional primary cell-based HSEs have transitioned to more standardized and reproducible in vitro culture models. These models utilize either immortalized cell lines [45] or cells derived from hiPSCs [17].”
From Diversity of human skin three-dimensional organotypic cultures (2024) · cites this paper as [17]
Reconstruction of appendage-bearing skin in cultures and in bioengineered grafts remains an unmet biomedical challenge.
“Reconstruction of appendage-bearing skin in cultures and in bioengineered grafts remains an unmet biomedical challenge3–9.”
From Hair-bearing human skin generated entirely from pluripotent stem cells (2020) · cites this paper as [6]
In vitro skin derivation strategies have focused on generating keratinocytes and fibroblasts from pluripotent stem cells in separate cultures first, then combining the two cell types to form a skin-like bilayer.
“To date, in vitro skin derivation strategies have focused on generating keratinocytes and fibroblasts from PSCs in separate cultures first, then combining the two types of cells to form a skin-like bilayer (Gledhill et al., 2015; Itoh et al., 2013; Oh et al., 2013; Sun et al., 2014).”
From Hair Follicle Development in Mouse Pluripotent Stem Cell-Derived Skin Organoids (2018) · cites this paper as Itoh et al., 2013
The logic of these approaches is that the individual parts can be combined to generate full-thickness skin.
“The logic of these approaches is that the individual parts can be combined to generate full-thickness skin (Itoh et al., 2013).”
From Hair Follicle Development in Mouse Pluripotent Stem Cell-Derived Skin Organoids (2018) · cites this paper as Itoh et al., 2013
Healthy cells can be generated from reprogrammed cells from patients with RDEB.
“and that healthy cells can be generated from reprogrammed cells from patients with RDEB (153, 154).”
From Wound repair and regeneration: Mechanisms, signaling, and translation (2014) · cites this paper as [153]
Human skin equivalents can be created entirely from fibroblasts and keratinocytes generated from patients' iPSCs.
“It has been shown that human skin equivalents can be created entirely from fibroblasts and keratinocytes generated from patients’ iPSCs, and that healthy cells can be generated from reprogrammed cells from patients with RDEB (153, 154).”
From Wound repair and regeneration: Mechanisms, signaling, and translation (2014) · cites this paper as [153]
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- Authors
- Itoh, M., Umegaki-Arao, N., Guo, Z., Liu, L., Higgins, C. A., & Christiano, A. M.
- Affiliations
- Columbia University (US)
- Corresponding author
- Christiano, Angela M.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-10-11
- Volume
- 8
- Issue
- 10
- Pages
- e77673
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3795682
- OpenAlex
- W1981286729
- Cited by
- 239
- References
- 42
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 21 · 2023: 16 · 2022: 24 · 2021: 22 · 2020: 18 · 2019: 20 · 2018: 25 · 2017: 23 · 2016: 10 · 2015: 16 · 2014: 18 · 2013: 1
- FWCI
- 6.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Columbia Academic Commons (Columbia University)
- Funders
- New York State Foundation for Science, Technology and Innovation
- Leona M. and Harry B. Helmsley Charitable Trust
- New York State Stem Cell Science
- Stanford Diabetes Research Center
- National Institutes of Health (U18TR000561)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR044535)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Health Sciences › Medicine › Urology › Hair Growth and Disorders
- Keywords
- induced pluripotent stem cells, 3D skin equivalents, dermal fibroblasts, keratinocytes, recessive dystrophic epidermolysis bullosa, COL7A1, type VII collagen, iPSC differentiation, regenerative therapy, patient-derived iPSCs
- MeSH terms
- Cell Differentiation, Cells, Cultured, Fibroblasts, Flow Cytometry, Humans, Skin, Blotting, Western, Keratinocytes, Reverse Transcriptase Polymerase Chain Reaction, Induced Pluripotent Stem Cells
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