AccScience Publishing / IJB / Online First / DOI: 10.36922/IJB026300321
Cite this article
28
Download
405
Views
Related Info Links
More by Authors Links
Journal Browser
Volume | Year
Issue
Search
News and Announcements
View All
REVIEW ARTICLE

Reconstructing hair follicle pigmentary unit using organoids and bioprinting

Qiaoli Xie1†* Zhuojun Liu1† Yijia Zhang1 Meiling Ren1 Bolin Chen1 Fanrun Zeng1 Xueli Han1 Ruoqi Zhou1 Chuqing Zhou1 Xiao Xiang1 Mingxing Lei1*
Show Less
1 Key Laboratory of Biorheological Science and Technology of Ministry of Education & 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing , China
†These authors contributed equally to this work.
Received: 25 July 2026 | Revised: 15 August 2026 | Accepted: 21 August 2026 | Published online: 21 August 2026
(This article belongs to the Special Issue 3D Bioprinting for Engineered Tissues and Organs)
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Abstract

Hair graying is a common feature of physiological aging and is typically evaluated by hair color, melanin content, or melanogenesis-related enzyme activity. However, growing evidence suggests that hair graying results from functional defects at multiple levels of the hair follicle pigmentary unit (HFPU). The HFPU comprises both the intrinsic melanocyte lineage and the extrinsic microenvironment that supports melanocyte function. Here, we review the application of emerging technologies, including organoids, biomaterials, bioprinting, and microphysiological systems, to HFPU reconstruction. Based on the biological functions directly demonstrated by different models, we define six ascending levels of evidence: pigment production, melanocyte differentiation, pigment transfer, progenitor cell maintenance, niche reconstruction, and durable or cycle-like regenerative capacity. Current three-dimensional models reproduce selected structural or cellular components of the HFPU, but remain limited in their ability to sustain melanocyte-lineage renewal, support coordinated pigment transfer, and restore pigmentary function after perturbation. Distinguishing transient hair darkening or short-term melanogenic activation from functional HFPU reconstruction gives a more rigorous evaluation of hair repigmentation models and the interventions tested using these models.

Graphical abstract
Keywords
Hair follicle pigmentary unit
Hair graying
Hair repigmentation
Melanocyte stem cells
Skin organoids
Bioprinting
Extracellular matrix
Mechanobiology
Funding
This work was supported by the National Key Research and Development Program of China (2023YFC2508200); the National Natural Science Foundation of China (82373509, 82574005); the Natural Science Foundation of Chongqing, China (CSTB2023NSCQ-MSX0463); and the Fundamental Research Funds for the Central Universities (2024CDJQYJCYJ-001).
Conflict of interest
The authors declare that there are no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
References
  1. Tobin DJ, Paus R. Graying: Gerontobiology of the hair follicle pigmentary unit. Exp Gerontol. 2001;36(1):29-54. doi: 10.1016/S0531-5565(00)00210-2
  2. Slominski A, Wortsman J, Plonka PM, Schallreuter KU, Paus R, Tobin DJ. Hair follicle pigmentation. J Invest Dermatol. 2005;124(1):13-21. doi: 10.1111/j.0022-202X.2004.23528.x
  3. O'Sullivan JDB, Nicu C, Picard M, et al. The biology of human hair greying. Biol Rev Camb Philos Soc. 2021;96(1):107-128. doi: 10.1111/brv.12648
  4. Qiu W, Chuong CM, Lei M. Regulation of melanocyte stem cells in the pigmentation of skin and its appendages: Biological patterning and therapeutic potentials. Exp Dermatol. 2019;28(4):395-405. doi: 10.1111/exd.13856
  5. Tobin DJ. The cell biology of human hair follicle pigmentation. Pigment Cell Melanoma Res. 2011;24(1):75-88. doi: 10.1111/j.1755-148X.2010.00803.x
  6. Rabbani P, Takeo M, Chou W, et al. Coordinated activation of Wnt in epithelial and melanocyte stem cells initiates pigmented hair regeneration. Cell. 2011;145(6):941-955. doi: 10.1016/j.cell.2011.05.004
  7. Nishimura EK, Granter SR, Fisher DE. Mechanisms of hair graying: Incomplete melanocyte stem cell maintenance in the niche. Science. 2005;307(5710):720-724. doi: 10.1126/science.1099593
  8. Inomata K, Aoto T, Binh NT, et al. Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation. Cell. 2009;137(6):1088-1099. doi: 10.1016/j.cell.2009.03.037
  9. Rosenberg AM, Rausser S, Ren J, et al. Quantitative mapping of human hair greying and reversal in relation to life stress. Elife. 2021;10:e67437. doi: 10.7554/eLife.67437
  10. Lei M, Schumacher LJ, Lai YC, et al. Self-organization process in newborn skin organoid formation inspires strategy to restore hair regeneration of adult cells. Proc Natl Acad Sci USA. 2017;114(34):E7101-E7110. doi: 10.1073/pnas.1700475114
  11. Lee J, Rabbani CC, Gao H, et al. Hair-bearing human skin generated entirely from pluripotent stem cells. Nature. 2020;582(7812):399-404. doi: 10.1038/s41586-020-2352-3
  12. Nanmo A, Yan L, Asaba T, et al. Bioprinting of hair follicle germs for hair regenerative medicine. Acta Biomater. 2023;165:50-59. doi: 10.1016/j.actbio.2022.06.021
  13. Lee J, van der Valk WH, Serdy SA, et al. Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells. Nat Protoc. 2022;17(5):1266-1305. doi: 10.1038/s41596-022-00681-y
  14. Li T, Li X, Xiang X, et al. Regenerative hair pigmentation via skin organoids: Adaptive patterning mediated by collagen VI and semaphorin 3C. Adv Sci (Weinh). 2025;12(36):e02436. doi: 10.1002/advs.202502436
  15. Qiu W, Gu PR, Chuong CM, Lei M. Skin cyst: A pathological dead-end with a new twist of morphogenetic potentials in organoid cultures. Front Cell Dev Biol. 2021;8:628114. doi: 10.3389/fcell.2020.628114
  16. Zou Y, Tang F, Li P, Qiu W, Lei M. Wnt10b regulation of hair follicle development, regeneration, and skin diseases. Stem Cell Rev Rep. 2025;21(6):1728-1737. doi: 10.1007/s12015-025-10898-5
  17. Tu S, Kageyama T, Seo J, Zhou Y, Fukuda J. Development of an in vitro hair pigmentation model using hair follicle organoids. J Biosci Bioeng. 2025;139(2):141-146. doi: 10.1016/j.jbiosc.2024.11.003
  18. Jeong S, Na Y, Nam HM, Sung GY. Skin-on-a-chip strategies for human hair follicle regeneration. Exp Dermatol. 2023;32(1):13-23. doi: 10.1111/exd.14699
  19. Commo S, Gaillard O, Bernard BA. Human hair greying is linked to a specific depletion of hair follicle melanocytes affecting both the bulb and the outer root sheath. Br J Dermatol. 2004;150(3):435-443. doi: 10.1046/j.1365-2133.2004.05787.x
  20. Paus R, Sevilla A, Grichnik JM. Human hair graying revisited: Principles, misconceptions, and key research frontiers. J Invest Dermatol. 2024;144(3):474-491. doi: 10.1016/j.jid.2023.09.276
  21. Sun Q, Lee W, Hu H, et al. Dedifferentiation maintains melanocyte stem cells in a dynamic niche. Nature. 2023;616(7958):774-782. doi: 10.1038/s41586-023-05960-6
  22. Nishimura EK, Suzuki M, Igras V, et al. Key roles for transforming growth factor beta in melanocyte stem cell maintenance. Cell Stem Cell. 2010;6(2):130-140. doi: 10.1016/j.stem.2009.12.010
  23. Wood JM, Decker H, Hartmann H, et al. Senile hair graying: H2O2-mediated oxidative stress affects human hair color by blunting methionine sulfoxide repair. FASEB J. 2009;23(7):2065-2075. doi: 10.1096/fj.08-125435
  24. Zhang B, Ma S, Rachmin I, et al. Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells. Nature. 2020;577(7792):676-681. doi: 10.1038/s41586-020-1935-3
  25. Nishimura EK, Jordan SA, Oshima H, et al. Dominant role of the niche in melanocyte stem-cell fate determination. Nature. 2002;416(6883):854-860. doi: 10.1038/416854a
  26. Higgins CA, Chen JC, Cerise JE, Jahoda CA, Christiano AM. Microenvironmental reprogramming by three-dimensional culture enables dermal papilla cells to induce de novo human hair-follicle growth. Proc Natl Acad Sci USA. 2013;110(49):19679-19688. doi: 10.1073/pnas.1309970110
  27. Nishimura EK. Melanocyte stem cells: A melanocyte reservoir in hair follicles for hair and skin pigmentation. Pigment Cell Melanoma Res. 2011;24(3):401-410. doi: 10.1111/j.1755-148X.2011.00855.x
  28. Wu X, Hammer JA. Melanosome transfer: It is best to give and receive. Curr Opin Cell Biol. 2014;29:1-7. doi: 10.1016/j.ceb.2014.02.003
  29. Abaci HE, Coffman A, Doucet Y, et al. Tissue engineering of human hair follicles using a biomimetic developmental approach. Nat Commun. 2018;9(1):5301. doi: 10.1038/s41467-018-07579-y
  30. Toyoshima KE, Asakawa K, Ishibashi N, et al. Fully functional hair follicle regeneration through the rearrangement of stem cells and their niches. Nat Commun. 2012;3:784. doi: 10.1038/ncomms1784
  31. Ando H, Niki Y, Yoshida M, et al. Involvement of pigment globules containing multiple melanosomes in the transfer of melanosomes from melanocytes to keratinocytes. Cell Logist. 2011;1(1):12-20. doi: 10.4161/cl.1.1.13638
  32. Wu XS, Masedunskas A, Weigert R, Copeland NG, Jenkins NA, Hammer JA. Melanoregulin regulates a shedding mechanism that drives melanosome transfer from melanocytes to keratinocytes. Proc Natl Acad Sci USA. 2012;109(31):E2101-E2109. doi: 10.1073/pnas.1209397109
  33. Chaudhuri O, Gu L, Darnell M, et al. Hydrogels with tunable stress relaxation regulate stem cell fate and activity. Nat Mater. 2016;15(3):326-334. doi: 10.1038/nmat4489
  34. Wang M, Zhou X, Zhou S, et al. Mechanical force drives the initial mesenchymal-epithelial interaction during skin organoid development. Theranostics. 2023;13(9):2930-2945. doi: 10.7150/thno.83217
  35. Lei M, Harn HI, Li Q, et al. The mechano-chemical circuit drives skin organoid self-organization. Proc Natl Acad Sci USA. 2023;120(36):e2221982120. doi: 10.1073/pnas.2221982120
  36. Ouyang L. Pushing the rheological and mechanical boundaries of extrusion-based 3D bioprinting. Trends Biotechnol. 2022;40(7):891-902. doi: 10.1016/j.tibtech.2022.01.001
  37. Blaeser A, Duarte Campos DF, Puster U, Richtering W, Stevens MM, Fischer H. Controlling shear stress in 3D bioprinting is a key factor to balance printing resolution and stem cell integrity. Adv Healthc Mater. 2016;5(3):326-333. doi: 10.1002/adhm.201500677
  38. Botchkareva NV, Khlgatian M, Longley BJ, Botchkarev VA, Gilchrest BA. SCF/c-kit signaling is required for cyclic regeneration of the hair pigmentation unit. FASEB J. 2001;15(3):645-658. doi: 10.1096/fj.00-0368com
  39. Ando H, Niki Y, Ito M, et al. Melanosomes are transferred from melanocytes to keratinocytes through the processes of packaging, release, uptake, and dispersion. J Invest Dermatol. 2012;132(4):1222-1229. doi: 10.1038/jid.2011.413
  40. Li H, Fan L, Zhu S, et al. Epilation induces hair and skin pigmentation through an EDN3/EDNRB-dependent regenerative response of melanocyte stem cells. Sci Rep. 2017;7(1):7272. doi: 10.1038/s41598-017-07683-x
  41. Liu H, Gan Z, Qin X, Wang Y, Qin J. Advances in microfluidic technologies in organoid research. Adv Healthc Mater. 2024;13(21):e2302686. doi: 10.1002/adhm.202302686
  42. Cao X, Xu D, Lu M, Zhao Y. Hair follicle seedling cryomicroneedles from hierarchical microfluidic organoid on a chip. Adv Sci (Weinh). Published online June 4, 2026. doi: 10.1002/advs.75961
  43. Ataç B, Kiss FM, Lam T, et al. The microfollicle: A model of the human hair follicle for in vitro studies. In Vitro Cell Dev Biol Anim. 2020;56(10):847-858. doi: 10.1007/s11626-020-00513-x
  44. Baltazar T, Jiang B, Moncayo A, et al. 3D bioprinting of an implantable xeno-free vascularized human skin graft. Bioeng Transl Med. 2023;8(1):e10324. doi: 10.1002/btm2.10324
  45. Zhao W, Chen H, Zhang Y, et al. Adaptive multi-degree-of-freedom in situ bioprinting robot for hair-follicle-inclusive skin repair: A preliminary study conducted in mice. Bioeng Transl Med. 2022;7(3):e10303. doi: 10.1002/btm2.10303
  46. Lei M, Jiang J, Wang M, et al. Epidermal-dermal coupled spheroids are important for tissue pattern regeneration in reconstituted skin explant cultures. NPJ Regen Med. 2023;8(1):65. doi: 10.1038/s41536-023-00340-0
  47. Lee V, Singh G, Trasatti JP, et al. Design and fabrication of human skin by three-dimensional bioprinting. Tissue Eng Part C Methods. 2014;20(6):473-484. doi: 10.1089/ten.TEC.2013.0335
  48. Catarino CM, Schuck DC, Dechiario L, Karande P. Incorporation of hair follicles in 3D bioprinted models of human skin. Sci Adv. 2023;9(41):eadg0297. doi: 10.1126/sciadv.adg0297
  49. Nasehi R, Aveic S, Fischer H. Wall shear stress during impingement at the building platform can exceed nozzle wall shear stress in microvalve-based bioprinting. Int J Bioprint. 2023;9(4):743. doi: 10.18063/ijb.743
  50. Kang MS, Kwon M, Lee SH, et al. 3D printing of skin equivalents with hair follicle structures and epidermal-papillary-dermal layers using gelatin/hyaluronic acid hydrogels. Chem Asian J. 2022;17(18):e202200620. doi: 10.1002/asia.202200620
  51. Kang D, Liu Z, Qian C, et al. 3D bioprinting of a gelatin-alginate hydrogel for tissue-engineered hair follicle regeneration. Acta Biomater. 2023;165:19-30. doi: 10.1016/j.actbio.2022.03.011
  52. Min D, Lee W, Bae IH, Lee TR, Croce P, Yoo SS. Bioprinting of biomimetic skin containing melanocytes. Exp Dermatol. 2018;27(5):453-459. doi: 10.1111/exd.13376
  53. Baltazar T, Merola J, Catarino C, et al. Three dimensional bioprinting of a vascularized and perfusable skin graft using human keratinocytes, fibroblasts, pericytes, and endothelial cells. Tissue Eng Part A. 2020;26(5-6):227-238. doi: 10.1089/ten.TEA.2019.0201
  54. Chen H, Zhang Y, Zhou D, Ma X, Yang S, Xu T. Mechanical engineering of hair follicle regeneration by in situ bioprinting. Biomater Adv. 2022;142:213127. doi: 10.1016/j.bioadv.2022.213127
  55. Chen H, Ma X, Gao T, Zhao W, Xu T, Liu Z. Robot-assisted in situ bioprinting of gelatin methacrylate hydrogels with stem cells induces hair follicle-inclusive skin regeneration. Biomed Pharmacother. 2023;157:114140. doi: 10.1016/j.biopha.2022.114140
  56. Ataç B, Wagner I, Horland R, et al. Skin and hair on-a-chip: In vitro skin models versus ex vivo tissue maintenance with dynamic perfusion. Lab Chip. 2013;13(18):3555-3561. doi: 10.1039/c3lc50227a
  57. Sugiyama E, Nanmo A, Nie X, et al. Large-scale preparation of hair follicle germs using a microfluidic device. ACS Biomater Sci Eng. 2024;10(2):998-1005. doi: 10.1021/acsbiomaterials.3c01346
  58. Osawa M, Egawa G, Mak SS, et al. Molecular characterization of melanocyte stem cells in their niche. Development. 2005;132(24):5589-5599. doi: 10.1242/dev.02161
  59. Singh SK, Nizard C, Kurfurst R, Bonte F, Schnebert S, Tobin DJ. The silver locus product (Silv/gp100/Pmel17) as a new tool for the analysis of melanosome transfer in human melanocyte-keratinocyte co-culture. Exp Dermatol. 2008;17(5):418-426. doi: 10.1111/j.1600-0625.2008.00702.x
  60. Chen CL, Huang WY, Wang EHC, Tai KY, Lin SJ. Functional complexity of hair follicle stem cell niche and therapeutic targeting of niche dysfunction for hair regeneration. J Biomed Sci. 2020;27(1):43. doi: 10.1186/s12929-020-0624-8
  61. Wu W, Zhou W, Jiang J, et al. Mechanical stimuli-induced CCL2 restores adult mouse cells to regenerate hair follicles. Mol Ther Nucleic Acids. 2023;32:94-110. doi: 10.1016/j.omtn.2023.03.002
  62. Zhou S, Li Z, Li X, et al. Crosstalk between endothelial cells and dermal papilla entails hair regeneration and angiogenesis during aging. J Adv Res. 2025;70:339-353. doi: 10.1016/j.jare.2024.05.006
  63. Nicu C, O'Sullivan JDB, Ramos R, et al. Dermal adipose tissue secretes HGF to promote human hair growth and pigmentation. J Invest Dermatol. 2021;141(7):1633-1645.e13. doi: 10.1016/j.jid.2020.12.019
  64. Yue Z, Lei M, Paus R, Chuong CM. The global regulatory logic of organ regeneration: Circuitry lessons from skin and its appendages. Biol Rev Camb Philos Soc. 2021;96(6):2573-2583. doi: 10.1111/brv.12767
  65. Ma X, Zhu X, Lv S, et al. 3D bioprinting of prefabricated artificial skin with multicomponent hydrogel for skin and hair follicle regeneration. Theranostics. 2025;15(7):2933-2950. doi: 10.7150/thno.104854
  66. Wu K, Wei J, Meng Z, Xu K, Lin JT. Harnessing the mechanical properties of gelatin methacryloyl hydrogels through cooling-induced entanglement. Theor Appl Mech Lett. 2025;15(6):100622. doi: 10.1016/j.taml.2025.100622
  67. Li ME, Jin C, Zhou J. Finite element implementation of poroelasticity theory for swelling dynamics of hydrogels. Theor Appl Mech Lett. 2013;3(5):054009. doi: 10.1063/2.1305409
  68. Sandoval AGW, Gim KY, Huang JT, Koehler KR. Applications of human pluripotent stem cell-derived skin organoids in dermatology. J Invest Dermatol. 2023;143(10):1872-1876. doi: 10.1016/j.jid.2023.07.017
  69. Dal Prà I, Chiarini A, De Santis D, Nocini R, Chang S, Armato U. The quest for the perfect healing of human skin wounds: Promising models. Regenesis Repair Rehabil. 2025;1(2):66-79. doi: 10.1016/j.rerere.2025.03.003
  70. Lin Z, Chen L, Qi C, Wang G. Skin microecology and skin barrier repair, wound healing and appendage regeneration. Regenesis Repair Rehabil. 2025;1(1):1-5. doi: 10.1016/j.rerere.2024.07.001
Share
Back to top
International Journal of Bioprinting, Electronic ISSN: 2424-8002 Print ISSN: 2424-7723, Published by AccScience Publishing