Using bioprinting and spheroid culture to create a skin model with sweat glands and hair follicles
Open accessAbstract
Background: Sweat glands (SGs) and hair follicles (HFs) are two important cutaneous appendages that play crucial roles in homeostatic maintenance and thermoregulation, and their interaction is involved in wound healing. SGs can be regenerated from mesenchymal stem cell-laden 3D bioprinted scaffolds, based on our previous studies, whereas regeneration of HFs could not be achieved in the same model. Due to the lack of an in vitro model, the underlying molecular mechanism of the interaction between SGs and HFs in regeneration could not be fully understood. The purpose of the present study was to establish an in vitro model of skin constructs with SGs and HFs and explore the interaction between these two appendages in regeneration. Methods: To investigate the interaction effects between SGs and HFs during their regeneration processes, a combined model was created by seeding HF spheroids on 3D printed SG scaffolds. The interaction between SG scaffolds and HF spheroids was detected using RNA expression and immunofluorescence staining. The effects of microenvironmental cues on SG and HF regeneration were analysed by altering seed cell types and plantar dermis homogenate in the scaffold. Results: According to this model, we overcame the difficulties in simultaneously inducing SG and HF regeneration and explored the interaction effects between SG scaffolds and HF spheroids. Surprisingly, HF spheroids promoted both SG and HF differentiation in SG scaffolds, while SG scaffolds promoted SG differentiation but had little effect on HF potency in HF spheroids. Specifically, microenvironmental factors (plantar dermis homogenate) in SG scaffolds effectively promoted SG and HF genesis in HF spheroids, no matter what the seed cell type in SG scaffolds was, and the promotion effects were persistent. Conclusions: Our approach elucidated a new model for SG and HF formation in vitro and provided an applicable platform to investigate the interaction between SGs and HFs in vitro. This platform might facilitate 3D skin constructs with multiple appendages and unveil the spatiotemporal molecular program of multiple appendage regeneration.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
HSE composition and culture conditions vary greatly from lab to lab, which can affect interpretation of similar experiments.
“their composition and culture conditions vary greatly from lab to lab, which can affect interpretation of similar experiments.”
From Single-cell transcriptomics of human-skin-equivalent organoids (2023) · cites this paper as [11]
The Background (page unavailable) identifies reproducible skin constructs as an unresolved challenge, and the Discussion (page unavailable) describes limitations of this paper’s own culture conditions. Neither passage says that HSE composition and culture conditions vary greatly between laboratories or that such variation affects interpretation of similar experiments. Searches for interlaboratory variation and interpretation found no passage addressing that claim. (LLM, conf=0.72)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Printing three-dimensional tissue analogues with decellularized extracellular matrix bioink
Pati, F., Jang, J., Ha, D.-H., Won Kim, S., Rhie, J.-W., Shim, J.-H., Kim, D.-H., & Cho, D.-W. (2014) · Nature Communications · doi:10.1038/ncomms4935 · Cited by 1,904 · see citing works
Lu, C. P., Polak, L., Rocha, A. S., Pasolli, H. A., Chen, S.-C., Sharma, N., Blanpain, C., & Fuchs, E. (2012) · Cell · doi:10.1016/j.cell.2012.04.045 · Cited by 301 · cited 2× · see citing works
“Until now, knowledge about the postnatal regeneration of multiple skin appendages has mostly come from studies in animal models [24,31].”
BackgroundMethodLei, M., Schumacher, L. J., Lai, Y.-C., Juan, W.-T., Yeh, C.-Y., Wu, P., Jiang, T.-X., Baker, R. E., Widelitz, R. B., Yang, L., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1700475114 · Cited by 142 · cited 4× · see citing works
“Although in vitro fabrication of SGs or HFs is feasible, there is, as of yet, no ideal model to mimic their physiologically symbiotic condition within actual skin [13,14].”
BackgroundMethodInfluentialSweat gland organoids contribute to cutaneous wound healing and sweat gland regeneration
Diao, J., Liu, J., Wang, S., Chang, M., Wang, X., Guo, B., Yu, Q., Yan, F., Su, Y., & Wang, Y. (2019) · Cell Death & Disease · doi:10.1038/s41419-019-1485-5 · Cited by 92 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 29
- [1]Quinby WC Jr, Burke JF, Bondoc CC. Primary excision and immediate wound closure. Intensive Care Med. 1981; 7: 71– 6. 7009690
- [2]Wang Y, Beekman J, Hew J, Jackson S, Issler-Fisher AC, Parungao R, et al. Burn injury: challenges and advances in burn wound healing, infection, pain and scarring. Adv Drug Deliv Rev. 2018; 123: 3– 17. 28941987
- [3]Kim HS, Sun X, Lee JH, Kim HW, Fu X, Leong KW. Advanced drug delivery systems and artificial skin grafts for skin wound healing. Adv Drug Deliv Rev. 2019; 146: 209– 39. 30605737
- [4]Murphy SV, Atala A. 3D bioprinting of tissues and organs. Nat Biotechnol. 2014; 32: 773– 85. 25093879
- [5]Zhou F, Hong Y, Liang R, Zhang X, Liao Y, Jiang D, et al. Rapid printing of bio-inspired 3D tissue constructs for skin regeneration. Biomaterials. 2020; 258: 120287. doi: 10.1016/j.biomaterials.2020.120287. 32847683 · DOI
- [6]Noor N, Shapira A, Edri R, Gal I, Wertheim L, Dvir T. 3D printing of personalized thick and perfusable cardiac patches and hearts. Adv Sci (Weinh). 2019; 6: 1900344. doi: 10.1002/advs.201900344. 31179230 PMC6548966 · DOI · Paper page
- [7]Varkey M, Visscher DO, van Zuijlen PPM, Atala A, Yoo JJ. Skin bioprinting: the future of burn wound reconstruction? Burns Trauma. 2019; 7: 4. doi: 10.1186/s41038-019-0142-7. 30805375 PMC6371568 · DOI
- [8]Tottoli EM, Dorati R, Genta I, Chiesa E, Pisani S, Conti B. Skin wound healing process and new emerging technologies for skin wound care and regeneration. Pharmaceutics. 2020; 12. doi: 10.3390/pharmaceutics12080735. PMC7463929 32764269 · DOI
- [10]Lee LF, Jiang TX, Garner W, Chuong CM. A simplified procedure to reconstitute hair-producing skin. Tissue Eng Part C Methods. 2011; 17: 391– 400. 21034159 PMC3065728
- [11]Lu C, Fuchs E. Sweat gland progenitors in development, homeostasis, and wound repair. Cold Spring Harb Perspect Med. 2014; 4. doi: 10.1101/cshperspect.a015222. PMC3904096 24492848 · DOI
- [12]Wang X, Tredget EE, Wu Y. dynamic signals for hair follicle development and regeneration. Stem Cells Dev. 2012; 21: 7– 18. 21787229
- [13]Yao B, Wang R, Wang Y, Zhang Y, Hu T, Song W, et al. Biochemical and structural cues of 3D-printed matrix synergistically direct MSC differentiation for functional sweat gland regeneration. Sci Adv. 2020; 6, 10: eaaz1094. doi: 10.1126/sciadv.aaz1094. 32181358 PMC7056319 · DOI
- [15]Lu CP, Polak L, Keyes BE, Fuchs E. Spatiotemporal antagonism in mesenchymal-epithelial signaling in sweat versus hair fate decision. Science. 2016; 354: aah6102. doi: 10.1126/science.aah6102. 28008008 PMC5333576 · DOI · Paper page
- [17]Lee CH, Rodeo SA, Fortier LA, Lu C, Erisken C, Mao JJ. Protein-releasing polymeric scaffolds induce fibrochondrocytic differentiation of endogenous cells for knee meniscus regeneration in sheep. Sci Transl Med. 2014; 6: 266ra171. doi: 10.1126/scitranslmed.3009696. PMC4546837 25504882 · DOI
- [18]Ma Y, Lin M, Huang G, Li Y, Wang S, Bai G, et al. 3D spatiotemporal mechanical microenvironment: a hydrogel-based platform for guiding stem cell fate. Adv Mater. 2018; 30: e1705911. doi: 10.1002/adma.201705911. 30063260 · DOI
- [19]West-Livingston LN, Park J, Lee SJ, Atala A, Yoo JJ. The role of the microenvironment in controlling the fate of bioprinted stem cells. Chem Rev. 2020; 120: 11056– 92. 32558555 PMC7676498
- [20]Wang R, Wang Y, Yao B, Hu T, Li Z, Liu Y, et al. Redirecting differentiation of mammary progenitor cells by 3D bioprinted sweat gland microenvironment. Burns Trauma. 2019; 7: 29. doi: 10.1186/s41038-019-0167-y. 31559316 PMC6755689 · DOI
- [21]Abaci HE, Coffman A, Doucet Y, Chen J, Jackow J, Wang E, et al. Tissue engineering of human hair follicles using a biomimetic developmental approach. Nat Commun. 2018; 9: 5301. doi: 10.1038/s41467-018-07579-y. 30546011 PMC6294003 · DOI · Paper page
- [22]Chen R, Zhu Z, Ji S, Geng Z, Hou Q, Sun X, et al. Sweat gland regeneration: current strategies and future opportunities. Biomaterials. 2020; 255: 120201. doi: 10.1016/j.biomaterials.2020.120201. 32592872 · DOI
- [23]Ito M, Yang Z, Andl T, Cui C, Kim N, Millar SE, et al. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature. 2007; 447: 316– 20. 17507982
- [25]Cui C-Y, Ishii R, Campbell DP, Michel M, Piao Y, Kume T, et al. Foxc1 ablated mice are anhidrotic and recapitulate features of human miliaria sweat retention disorder. J Invest Dermatol. 2017; 137: 38– 45. 27592801 PMC5183533
- [26]Tong X, Coulombe PA. Keratin 17 modulates hair follicle cycling in a TNFalpha-dependent fashion. Genes Dev. 2006; 20: 1353– 64. 16702408 PMC1472909
- [27]Shimomura Y, Wajid M, Shapiro L, Christiano AM. P-cadherin is a p63 target gene with a crucial role in the developing human limb bud and hair follicle. Development. 2008; 135: 743– 53. 18199584
- [28]Fuchs E. Scratching the surface of skin development. Nature. 2007; 445: 834– 42. 17314969 PMC2405926
- [29]Meng F, Meyer CM, Joung D, Vallera DA, McAlpine MC, Panoskaltsis-Mortari A. 3D bioprinted in vitro metastatic models via reconstruction of tumor microenvironments. Adv Mat. 2019; 31: e1806899. doi: 10.1002/adma.201806899. PMC6996245 30663123 · DOI · Paper page
- [30]Yan WC, Davoodi P, Vijayavenkataraman S, Tian Y, Ng WC, Fuh JYH, et al. 3D bioprinting of skin tissue: from pre-processing to final product evaluation. Adv Drug Deliv Rev. 2018; 132: 270– 95. 30055210
- [31]Wang X, Chen H, Tian R, Zhang Y, Drutskaya MS, Wang C, et al. Macrophages induce AKT/beta-catenin-dependent Lgr5(+) stem cell activation and hair follicle regeneration through TNF. Nat Commun. 2017; 8: 14091. doi: 10.1038/ncomms14091. 28345588 PMC5378973 · DOI
- [32]Huang S, Yao B, Xie J, Fu X. 3D bioprinted extracellular matrix mimics facilitate directed differentiation of epithelial progenitors for sweat gland regeneration. Acta Biomater. 2016; 32: 170– 7. 26747979
- [33]Huang S, Xu Y, Wu C, Sha D, Fu X. In vitro constitution and in vivo implantation of engineered skin constructs with sweat glands. Biomaterials. 2010; 31: 5520– 5. 20398932
Cited by
Sorted by citations
Single-cell transcriptomics of human-skin-equivalent organoids
Stabell, A. R., Lee, G. E., Jia, Y., Wong, K. N., Wang, S., Ling, J., Nguyen, S. D., Sen, G. L., Nie, Q., & Atwood, S. X. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112511 · Cited by 30 · see citing works
- Authors
- Zhang, Y., Enhejirigala, Yao, B., Li, Z., Song, W., Li, J., Zhu, D., Wang, Y., Duan, X., Yuan, X., Huang, S., & Fu, X.
- Affiliations
- Chinese PLA General Hospital (CN)
- Nankai University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Huang, Sha
- Fu, Xiaobing
- ORCID
- Venue
- Burns & Trauma
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-01-01
- Volume
- 9
- Pages
- tkab013-tkab013
- ISSN
- 2321-3868 (ISSN-L)
- 2321-3876
- PMC
- PMC8240535
- OpenAlex
- W3165182033
- Cited by
- 69
- References
- 4
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 16 · 2023: 17 · 2022: 13 · 2021: 5
- FWCI
- 14.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Burns & Trauma (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Nature Science Foundation of China (81830064, 81721092, 81701906)
- National Key Research and Development Plan (2017YFC1103300)
- Topics
- Health Sciences › Medicine › Urology › Hair Growth and Disorders
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- sweat glands, hair follicle, 3D bioprinting, spheroid culture, skin appendage regeneration, in vitro skin model, mesenchymal stem cells, microenvironmental cues, wound healing, thermoregulation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
