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Professor CHAN, Danny 陳振勝

Professor CHAN, Danny 陳振勝

  • BSc (Hon); MSc, PhD (U of Melbourne)
  • S Y and H Y Cheng Professor in Stem Cell Biology and Regenerative Medicine
  • Assistant Dean (Research postgraduate studies), Faculty of Medicine
  • Interim Director (School of Biomedical Sciences), Faculty of Medicine
  • Director (Education and Development of Research Integrity), HKU
L3-67, Laboratory Block, 21 Sassoon Road, Hong Kong
+852 3917 9482
+852 2855 1254
  • Understanding rare and common genetic diseases of the skeleton
    • Molecular and cellular consequences of genetic mutations and risk factors
    • Impact in development and growth from studies of mouse models
    • Therapeutic strategies through mechanistic insights
  • Role of the extracellular matrix (ECM) niche in stem cell maintenance and differentiation
    • Role of stem cell ECM niche in planarian regeneration
    • Discovering molecular signals and ECM in supporting in vivo and in vitro differentiation of progenitor cells along skeletal cell lineages
    • Identifying specific and optimal cell types for the repair of damaged skeletal tissues such as cartilage, bone and the intervertebral disc

Graduated from the University of Melbourne, with a Bachelor of Science (degree with honours), Master of Science and PhD, Prof. Chan continued research at his alma mater on heritable skeletal disorders with a focus on extracellular matrix proteins. He joined the University of Hong Kong in 1998, maintaining his research in skeletal biology using mouse as a model to address disease mechanisms in vivo, as well as human genetic studies to define genetic risk factors for common degenerative skeletal conditions such as intervertebral disc degeneration. His research contributed to the molecular understanding of many forms of the human osteochondrodysplasias.  In recognition, he was presented with “The Premier’s Award for Health & Medical Research in Victoria, Australia; and more recently, he received the Croucher Senior Fellowship from the Croucher Foundation as recognition of his contribution to skeletal research in Hong Kong.

My research interest is in skeletal biology, focusing on development, growth and degenerative processes of the skeleton in health and disease. The emphasis is on genes regulating the linear growth of long bones, the formation of a synovial joint, and the intervertebral disc of the spine. The approach is to identify novel disease genes and to model the disease in mice to define the precise molecular and developmental changes.

In addressing the molecular basis for metaphyseal chondrodysplasia type Schmid (MCDS), a human condition with an abnormal growth plate causing dwarfism, we showed that the consequence is from activating ER-stress signal in hypertrophic chondrocytes that induces a “reprogramming” event, and the cells become “rejuvenated” (22). We provided detailed analysis of the cellular outcome (11) and potential therapeutic options (4, 8).  Understanding this “reprogramming” progress not only has implications in the control of chondrocyte differentiation, but also regenerative strategies for degenerative cartilage and bone diseases.

A related goal is to understand the signals controlling joint formation, with an emphasis in the formation of digit joints. In address the molecular consequence of brachydactyly type A1 (BDA1), we provided novel insights into how mutations in the IHH gene alter the signaling capacity and range of hedgehog proteins, as these mutations impair IHH interaction with partner molecules (20). Through this, we identified a novel population of progenitor cells within the developing joint expressing Lgr5, and lineage tracing of these cells showed the progression to a Col22a1 expression juvenile articular cartilage chondrocyte (3). We propose that these are the “true” progenitor cells best suited for the repair of damaged cartilage in knee or other synovial joints.

I coordinate a Human Genetic Research Programme aiming to identify genetic risk factors for intervertebral disc (IVD) degeneration, a major cause of back pain. The aim is to understand the etiology of disc degeneration and a mean derive new strategies in the prevention and treatment of the disease. Through a candidate gene approach, we showed that Asporin (21) and CHST3 (14) as a new genetic risk factors for intervertebral disc degeneration We also use mouse as a model to understand the molecular and cellular basis of these risk factors. We also leverage on mouse genetics to identify protective factors in mice with good tissue healing potentials such as the LG/J or MRL strains (5), as well as the generation of progenitor cells as a treatment for intervertebral disc degeneration (1).

As my area of my expertise is in the extracellular matrix proteins; a new direction in my lab is to use the regenerative Planarian as a model organism to study the extracellular matrix niche of stem cell maintenance. Planarians have extraordinary potentials to regenerate missing body parts that could provide vital clues for the developing of novel regenerative strategies.

  • Molecular insights into rare and common genetic diseases of the skeleton
  • ECM niche in stem cell maintenance and differentiation

lab group photoLab group photoLab group photoLab group photo

Lab Group Gatherings

  1. Zhang Y, Zhang Z, Chen P, Ma CY, Li C, Au TYK, Tam V, Peng Y, Wu R, Cheung KMC, Sham PC, Tse HF, Chan D, Leung VY, Cheah KSE, Lian Q (2020) Directed Differentiation of Notochord-like and Nucleus Pulposus-like Cells Using Human Pluripotent Stem Cells. Cell Rep. 30(8):2791-2806.e5. doi:10.1016/j.celrep.2020.0100
  2. Gauci SJ, Golub SB, Tatarczuch L, Lee E, Chan D, Walsh NC, Little CB, Stanton H, Lokmic Z, Sims NA, Mackie EJ, Fosang AJ. (2019) Disrupted type II collagenolysis impairs angiogenesis, delays endochondral ossification and initiates aberrant ossification in mouse limbs. Matrix Biol. 83:77-96
  3. Feng C, Chan WCW, Lam Y, Wang X, Chen P, Niu B, Ng VCW, Yeo JC, Stricker S, Cheah KSE, Koch M, Mundlos S, Ng HH, Chan D. (2019) Lgr5 and Col22a1 Mark Progenitor Cells in the Lineage toward Juvenile Articular Chondrocytes. Stem Cell Reports 13(4):713-729
  4. Wang C, Tan Z, Niu B, Tsang KY, Tai A, Chan WCW, Lo RLK, Leung KKH, Dung NWF, Itoh N, Zhang MQ, Chan D, Cheah KSE (2018) Inhibiting the integrated stress response pathway prevents aberrant chondrocyte differentiation thereby alleviating chondrodysplasia. elife. 2018 Jul 19;7. pii: e37673. doi: 10.7554/eLife.37673
  5. Zhang Y, Xiong C, Kudelko M, Li Y, Wang C, Wong1YL, Tam V, Rai MF, Cheverud J, Lawson HA, Sandell L, Chan WCW, Cheah KSE, Sham PC, Chan D (2018) Early onset disc degeneration in SM/J mice is associated with ion transport systems and fibrotic changes. Matrix Biol. 70:123-139
  6. Tan Z, Niu B, Tsang KY, Melhado IG, Ohba, He SX, Huang Y, Wang C, McMahon AP, Jauch R, Chan D, Zhang MQ, Cheah KSE. (2018)  Synergistic co-regulation and competition by a SOX9-GLI-FOXA phasic transcriptional network coordinate chondrocyte differentiation transitions. PLoS Genet. 14(4): e1007346
  7. Chan WL, Steiner M, Witkos TM, Egerer1 J, Busse B, Mizumoto, Pestka J, Zhang H, Hausser I, Khayal1 LA,  Ott CE, Kolanczyk M, Willie B, Schinke T, Paganini C, Rossi A, Sugahara K, Amling M, Knaus P, Chan D, Lowe M, Mundlos S, Kornak U (2018) Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica. PLoS Genet 21;14(3):e1007242
  8. Chan WCW, Tsang KY, Cheng YW, Ng VCW, Chik H, Tan ZJ, Boot-Handford R, Boyde A, Cheung KMC, Cheah KSE, Chan D (2017) Activating the unfolded protein response in osteocytes causes hyperostosis consistent with craniodiaphyseal dysplasia. Human Mol Genet 26(23):4572-4587
  9. Wang Y, Wu MH, Cheung MPL, Sham MH, Akiyama H, Chan D, Cheah KSE, Cheung M. (2017) Reprogramming of Dermal Fibroblasts into Osteo-Chondrogenic Cells with Elevated Osteogenic Potency by Defined Transcription Factors. Stem Cell Reports. Jun 6;8(6):1587-1599
  10. Li Y, Samartzis D, Campbell DD, Cherny SS, Cheung KM, Luk KD, Karppinen J, Song Y, Cheah KS, Chan D, Sham PC (2016) Two subtypes of intervertebral disc degeneration distinguished by large-scale population-based study. Spine J. 16(9):1079-89
  11. Kudelko M, Chan CW, Sharma R, Yao Q, Lau E, Chu IK, Cheah KS, Tanner JA, Chan D (2016) Label-Free Quantitative Proteomics Reveals Survival Mechanisms Developed by Hypertrophic Chondrocytes under ER Stress. Mol Cell Proteomics. 15(1):86-99
  12. Yee A, Lam MP, Tam V, Chan WC, Chu IK, Cheah KS, Cheung KM, Chan D (2016) Fibrotic-like changes in degenerate human intervertebral discs revealed by quantitative proteomic analysis. Osteoarthritis Cartilage. 24(3):503-13
  13. Yang L, Tsang KY, Tang HC, Chan D, Cheah KSE (2014) Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. PNAS 19;111(33):12097-12102
  14. Song YQ, Karasugi T, Cheung KM, Chiba K, Ho DW, Miyake A, Kao PY, Sze KL, Yee A, Takahashi A, Kawaguchi Y, Mikami Y, Matsumoto M, Togawa D, Kanayama M, Shi D, Dai J, Jiang Q, Wu C, Tian W, Wang N, Leong  JC, Luk KD, Yip SP, Cherny SS, Wang J, Mundlos S, Kelempisioti A, Eskola PJ, Mannikko M, Makela P, Karppinen J, Jarvelin MR, O'Reilly PF, Kubo M, Kimura T, Kubo T, Toyama Y, Mizuta H, Cheah KS, Tsunoda T, Sham PC, Ikegawa S, Chan D (2013) Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant.  J. Clin. Invest 123:4909-4917
  15. Leung VY, Aladin DM, Lv F, Tam V, Sun Y, Lau, RY, Hung SC, Ngan AH, Tang B, Lim CT, Wu EX, Luk KD, Lu WW, Masuda K, Chan D, Cheung KM (2014) Mesenchymal stem cells reduce intervertebral disc fibrosis and facilitate repair. Stem Cells 32:2164-2177
  16. Sakai D, Nakamura Y, Nakai T, Mishima T, Kato S, Grad S, Alini M, Risbud M V, Chan D, Cheah KSE, Yamamura K, Masuda K, Okano H, Ando K, Mochida J (2012) Exhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc. Nat. Commun. 3:1264
  17. Spielmann M, Brancati F, Krawitz PM, Robinson PN, Ibrahim DM, Franke M, Hecht J, Lohan S, Dathe K, Nardone AM, Ferrari P, Landi A, Wittler L, Timmermann B, Chan D, Mennen U, Klopocki E, Mundlos S (2012) Homeotic arm-to-leg transformation associated with genomic rearrangements at the PITX1 locus. Am. J. Hum. Genet. 91:629-635
  18. Klopocki E, Lohan S, Brancati F, Koll R, Brehm A, Seemann P, Dathe K, Stricker S, Hecht J, Bosse K, Betz RC, Garaci FG, Dallapiccola B, Jain M, Muenke M, Ng VC, Chan W, Chan D, Mundlos S (2011) Copy-number variations involving the IHH locus are associated with syndactyly and craniosynostosis, Am. J. Hum. Genet. 88:70-75
  19. Witte F, Chan D, Economides AN, Mundlos S, Stricker S (2010) ROR2 and Indian hedgehog regulate digit outgrowth mediated by the phalanx-forming region. PNAS 107:14211-14216
  20. Gao B, Hu J, Stricker S, Cheung M, Ma G, Law KF, Witte F, Briscoe J, Mundlos S, He L, Cheah KSE, Chan D. (2009) A mutation in Ihh that causes digit abnormalities alters its signalling capacity and range. Nature 458:1196-1200
  21. Song YQ, Cheung KMC, Ho DWH, Poon SCS, Chiba K, Kawaguchi Y, Hirose Y, Alini M, Grad S, Yee AFY, Leong JCY, Luk KDK, Yip SP, Karppinen J, Cheah KSE, Sham P, Ikegawa S, Chan D. (2008) Association of the Asporin D14 allele with lumbar disc degeneration in Asians. Am. J. Human Genet. 82:744-747
  22. Tsang KY, Chan D**, Cheslett D, Chan WC, So CL, Melhado IG, Chan TW, Kwan KM, Hunziker EB, Yamada Y, Bateman JF, Cheung KM, Cheah KSE (2007) Surviving endoplasmic reticulum stress is coupled to altered chondrocyte differentiation and function. PLoS. Biol. 5:568-585

 

Book Chapters and reviews:

  1. Wang X, Chan WCW, Chan D (2016) Chapter 7: “Joint Development” pp169-190, Cartilage Vol 1: Physiology and Development; Susanne Grässel, Attila Aszódi, editors. Springer International Publishing
  2. Shah AM, Kwon SYJ, Chan WCW, Chan D (2017) Chapter 10: “Intervertebral Disc Degeneration pp 229-261, Cartilage Vol 2: Pathophysiology; Susanne Grässel, Attila Aszódi, editors. Springer International Publishing
  3. Tsang KY, Wa TS, Chan D, Cheah KS (2014). The chondrocytic journey in endochondral bone growth and skeletal dysplasia. Birth Defects Res. C. Embryo. Today 102:52-73
  4. Chan WC, Au TY, Tam V, Cheah KS, Chan D (2014) Coming together is a beginning: the making of an intervertebral disc. Birth Defects Res. C. Embryo. Today 102:83-100

Recent Research Funding:

Year Project Title Funding Source(s) Amount (HK$)
2016 IHH regulating CDO/GAS1 function in synovial joint formation GRF (RGC) 1,122,632
2017 Understanding hyperplastic callus and abnormal bone formation in osteogenesis imperefecta type V GRF (RGC) 959,452
2018 Molecular basis of Asporin as a genetic risk factor for intervertebral disc degeneration GRF (RGC) 704,862
2019 Exploiting the true joint progenitor cell for articular cartilage repair CRF (RGC) 7,370,585
2019 Induced pluripotent stem cell-based therapy for spinal regeneration (iPSpine) EU (RGC) 2,995,876
2019 Ligament and tendon repair using Lgr5+ interzone cells as progenitor HMRF 1,491,308
2019 Deciphering protective factors for intervertebral disc degeneration for mechanistic insights and intervention potentials GRF(RGC) 1,029,233
2019 Understanding FGF signaling to treat spinal defects (FANTASIA) ANR/RGC 2,994,529

 

  • Research Officer:
    • Dr Wilson Chan
  • Postdoctoral Fellow and Research Associates:
    • Dr Sophia Ma
    • Dr Vivian Tam
    • Dr Yan Lam
    • Dr Andy Chan
  • Research Assistants:
    • Ms Ting Mei
    • Ms Alice Tsui
  • Senior Technical Officer:
    • Ms Andrea Ng
  • Research Postgraduate Students:
    • William Lam (PhD)
    • Aqsa Rubab (PhD)
    • Winnie Tong (MPhil)
    • Fatima Tuz Zahra (PhD)
    • Mengxia Zhu (PhD)
    • Wing Lam Cheung (MPhil)
    • Divya Vimalagopalan (MPhil)

Last updated: 2020-07-03