• A Corrigendum to this article was published on 30 November 2016

Abstract

The repair and regeneration of tissues using endogenous stem cells represents an ultimate goal in regenerative medicine. To our knowledge, human lens regeneration has not yet been demonstrated. Currently, the only treatment for cataracts, the leading cause of blindness worldwide, is to extract the cataractous lens and implant an artificial intraocular lens. However, this procedure poses notable risks of complications. Here we isolate lens epithelial stem/progenitor cells (LECs) in mammals and show that Pax6 and Bmi1 are required for LEC renewal. We design a surgical method of cataract removal that preserves endogenous LECs and achieves functional lens regeneration in rabbits and macaques, as well as in human infants with cataracts. Our method differs conceptually from current practice, as it preserves endogenous LECs and their natural environment maximally, and regenerates lenses with visual function. Our approach demonstrates a novel treatment strategy for cataracts and provides a new paradigm for tissue regeneration using endogenous stem cells.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Lens and retina regeneration: new perspectives from model organisms. Biochem. J. 447, 321–334 (2012)

  2. 2.

    & Lens and retina regeneration: transdifferentiation, stem cells and clinical applications. Exp. Eye Res. 78, 161–172 (2004)

  3. 3.

    Lens regeneration in mammals: a review. Surv. Ophthalmol. 51, 51–62 (2006)

  4. 4.

    , & A histologic study of lens regeneration in aphakic rabbits. Invest. Ophthalmol. Vis. Sci. 31, 540–547 (1990)

  5. 5.

    et al. Global prevalence of vision impairment and blindness: magnitude and temporal trends, 1990–2010. Ophthalmology 120, 2377–2384 (2013)

  6. 6.

    , , & Posterior capsule opacification in mice. Arch. Ophthalmol. 123, 71–77 (2005)

  7. 7.

    , & Toric intraocular lenses: historical overview, patient selection, IOL calculation, surgical techniques, clinical outcomes, and complications. J. Cataract Refract. Surg. 39, 624–637 (2013)

  8. 8.

    , , , & Complications of foldable intraocular lenses requiring explantation or secondary intervention – 2003 survey update. J. Cataract Refract. Surg. 30, 2209–2218 (2004)

  9. 9.

    , & Multifocal intraocular lens implantation in pediatric cataract surgery. Ophthalmology 108, 1375–1380 (2001)

  10. 10.

    et al. One-year strabismus outcomes in the Infant Aphakia Treatment Study. Ophthalmology 120, 1227–1231 (2013)

  11. 11.

    Infant Aphakia Treatment Study Group. A randomized clinical trial comparing contact lens with intraocular lens correction of monocular aphakia during infancy: grating acuity and adverse events at age 1 year. Arch. Ophthalmol. 128, 810–818 (2010)

  12. 12.

    , & Oxidative damage and the prevention of age-related cataracts. Ophthalmic Res. 44, 155–165 (2010)

  13. 13.

    et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302–305 (2003)

  14. 14.

    & Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423, 255–260 (2003)

  15. 15.

    et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962–967 (2003)

  16. 16.

    Animal models in eye research . 1st edn, (Academic Press, 2008)

  17. 17.

    , & Blindness in childhood in developing countries: time for a reassessment? PLoS Med. 6, e1000177 (2009)

  18. 18.

    , & Pediatric Ophthalmology: Current Thought and A Practical Guide . (Springer-Verlag, Berlin, 2009)

  19. 19.

    et al. Visual impairment and delay in presentation for surgery in chinese pediatric patients with cataract. Ophthalmology 118, 17–23 (2011)

  20. 20.

    , & Pediatric Cataract Surgery: Techniques, Complications, and Management . (Lippincott Williams & Wilkins, 2005)

  21. 21.

    et al. Vitreous surgery for macular hole-related retinal detachment after phacoemulsification cataract extraction: 10-year retrospective review. Eye (Lond.) 26, 1058–1064 (2012)

  22. 22.

    , , & A hierarchy of proliferative cells exists in mouse lens epithelium: implications for lens maintenance. Invest. Ophthalmol. Vis. Sci. 47, 2997–3003 (2006)

  23. 23.

    et al. Complications, adverse events, and additional intraocular surgery 1 year after cataract surgery in the Infant Aphakia Treatment Study. Ophthalmology 118, 2330–2334 (2011)

  24. 24.

    & Technological advances in pediatric cataract surgery. Semin. Ophthalmol. 25, 271–274 (2010)

  25. 25.

    , & Restoring lens capsule integrity enhances lens regeneration in New Zealand albino rabbits and cats. J. Cataract Refract. Surg. 19, 735–746 (1993)

  26. 26.

    et al. Notch signaling regulates growth and differentiation in the mammalian lens. Dev. Biol. 321, 111–122 (2008)

  27. 27.

    et al. Prospective identification of functionally distinct stem cells and neurosphere-initiating cells in adult mouse forebrain. Elife 3, e02669 (2014)

  28. 28.

    et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nature Genet. 23, 99–103 (1999)

  29. 29.

    & Evaluation of infant accommodation using retinoscopy and photoretinoscopy. Optom. Vis. Sci. 86, 208–215 (2009)

  30. 30.

    , , & Development of accommodation and convergence in infancy. Behav. Brain Res. 49, 33–50 (1992)

  31. 31.

    The development of visual accommodation during early infancy. Child Dev. 51, 646–666 (1980)

Download references

Acknowledgements

We thank E. Yeh, L. Xi, J. Shelton, A. Pineda and R. Ufret-Vincenty for technical assistance. This study was funded by 973 Program (2015CB964600, 2014CB964900, 2013CB967504); a Major International Joint Research Project (No. 81320108008); 863 Program (2014AA021604), NSFC (No. 81270981); the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University; Research to Prevent Blindness and the Howard Hughes Medical Institute.

Author information

Author notes

    • Haotian Lin
    • , Hong Ouyang
    • , Jie Zhu
    •  & Shan Huang

    These authors contributed equally to this work.

Affiliations

  1. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China

    • Haotian Lin
    • , Hong Ouyang
    • , Shan Huang
    • , Zhenzhen Liu
    • , Shuyi Chen
    • , Xialin Liu
    • , Lixia Luo
    • , Baoxin Chen
    • , Jiangna Chen
    • , Fu Shang
    • , Xuri Li
    • , Yujuan Wang
    • , Zheng Zhong
    • , Kang Zhang
    •  & Yizhi Liu
  2. Shiley Eye Institute, Institute for Engineering in Medicine, Institute for Genomic Medicine, University of California, San Diego, La Jolla, California 92093, USA

    • Jie Zhu
    • , Christopher Chung
    • , Danni Lin
    • , Sherrina Patel
    • , Frances Wu
    • , Cindy Wen
    • , Maryam Jafari
    • , Jin Zhu
    • , Austin Qiu
    • , David Granet
    • , Christopher Heichel
    • , Michal Krawczyk
    • , Dorota Skowronska-Krawczyk
    • , William Shi
    • , Daniel Chen
    • , Zheng Zhong
    • , Sheng Zhong
    • , Liangfang Zhang
    • , Shaochen Chen
    •  & Kang Zhang
  3. Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China

    • Guiqun Cao
    • , Gen Li
    • , Yanxin Xu
    • , Huimin Cai
    •  & Kang Zhang
  4. Guangzhou KangRui Biological Pharmaceutical Technology Company, Guangzhou 510005, China

    • Gen Li
    • , Huimin Cai
    •  & Rui Hou
  5. Howard Hughes Medical Institute, Children’s Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

    • Robert A. J. Signer
    •  & Sean J. Morrison
  6. Department of Ophthalmology, West China Hospital, Sichuan University, Sichuan 610041, China

    • Yanxin Xu
  7. Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA

    • Ying Zhang
    •  & Richard L. Maas
  8. Clinical and Translational Research Institute, University of California, San Diego, La Jolla, California 92093, USA

    • Jiayi Hou
  9. Veterans Administration Healthcare System, San Diego, California 92093, USA

    • Kang Zhang

Authors

  1. Search for Haotian Lin in:

  2. Search for Hong Ouyang in:

  3. Search for Jie Zhu in:

  4. Search for Shan Huang in:

  5. Search for Zhenzhen Liu in:

  6. Search for Shuyi Chen in:

  7. Search for Guiqun Cao in:

  8. Search for Gen Li in:

  9. Search for Robert A. J. Signer in:

  10. Search for Yanxin Xu in:

  11. Search for Christopher Chung in:

  12. Search for Ying Zhang in:

  13. Search for Danni Lin in:

  14. Search for Sherrina Patel in:

  15. Search for Frances Wu in:

  16. Search for Huimin Cai in:

  17. Search for Jiayi Hou in:

  18. Search for Cindy Wen in:

  19. Search for Maryam Jafari in:

  20. Search for Xialin Liu in:

  21. Search for Lixia Luo in:

  22. Search for Jin Zhu in:

  23. Search for Austin Qiu in:

  24. Search for Rui Hou in:

  25. Search for Baoxin Chen in:

  26. Search for Jiangna Chen in:

  27. Search for David Granet in:

  28. Search for Christopher Heichel in:

  29. Search for Fu Shang in:

  30. Search for Xuri Li in:

  31. Search for Michal Krawczyk in:

  32. Search for Dorota Skowronska-Krawczyk in:

  33. Search for Yujuan Wang in:

  34. Search for William Shi in:

  35. Search for Daniel Chen in:

  36. Search for Zheng Zhong in:

  37. Search for Sheng Zhong in:

  38. Search for Liangfang Zhang in:

  39. Search for Shaochen Chen in:

  40. Search for Sean J. Morrison in:

  41. Search for Richard L. Maas in:

  42. Search for Kang Zhang in:

  43. Search for Yizhi Liu in:

Contributions

H.L., S.H., Z.L., S.C., .X.L., L.L., B.C., Y.W. and Y.L. conducted the clinical trial; H.O., Jie Z., Y.Z., J.C., H.C. and S.P. performed mouse LEC lineage tracing experiments; H.O., J.Z., G.C., G.L., Y.X., S.P., Jin Z., M.J., A.Q., F.S., X.L., R.H., W.S. and D.C. performed LEC characterization and differentiation experiments; D.G., C.H., F.W., Z.S. and J.H. analysed clinical trial data; H.O., M.K., D.S-K., C.C., M.J., Y.W., W.S., D.C., S.Z., L.Z. and S.C. performed gene expression studies and analysed data; R.A.J.S. and S.J.M. performed and analysed the experiments related to BMI-1 function in mouse lens epithelium. Y.L, R.M. and K.Z. designed the study and wrote the paper. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Kang Zhang or Yizhi Liu.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figure 1, which contains original gel pictures used in Figure 2, and Supplementary Table 1, which shows the sequences of primers used for real-time PCR.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature17181

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.