研究室簡介

本實驗室目前是利用多功能幹細胞(Pluripotent stem cells)作為模型來研究心臟傳導系統細胞(Cardiac conduction system cells) 的發育和分化。心臟傳導系統是由特殊化的心肌細胞所組成的傳導系統,包括竇房結、房室結、房室束、左右房室束分支及浦金氏纖維。這系統能夠啟動電位並將電位傳遞到整個心肌進而產生心臟的收縮跳動,因此當心臟傳導系統受損時就會導致心律不整的產生,而此疾病是目前世界發病率與死亡率最高的主要疾病之一。因此,如何找到有效的治療策略是目前非常重要的課題。多功能幹細胞能分化成各種不同的細胞,因此能被有效作為再生療法的重要來源。如何利用幹細胞分化來的心臟傳導系統細胞作為有效疾病機制的研究和藥物發現的疾病模型,進而用於再生療法提供新的細胞材料是本實驗室的目標。

本實驗室目前的主要方向是: 1)使用化學篩選(Chemical screening)的方法來找出能高效率的將小鼠和人的幹細胞分化到心臟傳導系統細胞的小分子和相關的訊息通路 。 2)使用病患的誘導多能幹細胞(induced pluripotent stem cells)或利用CRISPR-Cas9技術所產生的等基因系(Isogenic)的細胞來研究心血管的發育規範和分化和作為一個疾病的模式來找出治療的方法。

Laboratory

Our major interest is to use pluripotent stem cells (PSCs) as a model to investigate the specification and differentiation of cells that generate the cardiac conduction system (CCS). The CCS comprises a complex network of cells that orchestrates the initiation and propagation of a wave of electrical excitation throughout the myocardium, including sinoatrial (SA) nodal cells, atrioventrcular (AV) nodal cells, His bundle, and Purkinje fibers. Dysfunction of the CCS significantly impacts pathogenesis of arrhythmia, which is a major cause of morbidity and mortality worldwide. Hence, efficient strategies to derive CCS cells would facilitate disease models for mechanistic studies and drug discovery, and also provide new cellular materials for regenerative therapies.

Our lab focuses on 1) Identification of small molecules and associated pathways that efficiently control the directed differentiation from both mouse and human PSCs to CCS using chemical approaches. 2) Using patient specific induced pluripotent stem cells (iPSCs) or Crispr-Cas9 technologies to generate isogenic lines to study cardiovascular development and modeling disease.

代表著作

Publications

  1. Chang CC, Huang TL, Shimamoto Y, Tsai SY, Hsia KC. (2017) Regulation of mitotic spindle assembly factor NuMA by Importin-β. J Cell Biol. (In Press)
  2. Crespo M, Vilar E, Tsai SY, Chang K, Amin S, Srinivasan T, Zhang T, Pipalia NH, Chen HJ, Witherspoon M, Gordillo M, Xiang JZ, Maxfield FR, Lipkin S, Evans T, Chen S. (2017) Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing. Nat Med. Jul; 23(7):878-884.
  3. Tsai SY*, Chen S, and Evans T. (2017). Efficient Generation of Cardiac Purkinje-like Cells from Embryonic Stem Cells by Activating cAMP Signaling. Current Protoc Stem Cell Biol. 40:1F.16.1-1F.16.13. (* Corresponding author).
  4. Feng L*, Cook B*, Tsai SY*, Zhou T*, LaFlamme B, Evans T and Chen S. (2016). Discovery of a Small- Molecule BMP Sensitizer for Human Embryonic Stem Cell Differentiation. Cell Reports. 15(9):2063-2075. (* Co-first author)
  5. Tsai SY, Maass K, Lu J, Fishman G.I., Chen S, and Evans T. (2015). Efficient generation of cardiac purkinje cells from ESCs by Activating cAMP Signaling. Stem Cell Reports. pii: S2213-6711(15)00127-7.
  6. Simsek S, Zhou T, Robinson C.L., Tsai SY, Lin X, Hon J, Evans T and Chen S. (2016). Modeling cystic fibrosis using PSC-derived human pancreatic ductal epithelial cells. STEM CELLS Translational Medicine. In press.
  7. Turbendian HK*, Gordillo M*, Tsai SY, Lu J, Kang G, Liu TC, Tang A , Liu S, Glenn I. Fishman G.I., and Evans T. (2013). GATA factors efficiently direct cardiac fate from ESCs. Development. 140(8):1639-44. (Second author)
  8. Casalena G, Krick S, Daehn I, Yu L, Ju W, Shi S, Tsai SY, D'Agati V, Lindenmeyer M, Cohen CD, Schlondorff D, Bottinger EP. (2014) Mpv17 in mitochondria protects podocytes against mitochondrial dysfunction and apoptosis in vivo and in vitro. Am J Physiol Renal Physiol. 306(11):F1372-80.
  9. Tsai SY*, Sennett R*, Rezza A, Clavel C, Grisanti L, Zemla R, Najam S, Rendl M. (2014). Wnt/β-catenin signaling in dermal condensates is required for hair follicle formation. Dev Biol. 385(2):179-88. (* Co-first author)
  10. Grisanti L, Clavel C, Cai X, Rezza A, Tsai SY, Sennett R, Mumau M, Cai CL, Rendl M. (2012). Tbx18 Targets Dermal Condensates for Labeling, Isolation, and Gene Ablation during Embryonic Hair Follicle Formation. J Invest Dermatol. 133(2):344-53
  11. Tsai SY, Bouwman BA, Ang YS, Kim SJ, Lee DF, Lemischka IR and Rendl M. (2011). Single transcription factor reprogramming of hair follicle dermal papilla cells to induced pluripotent stem cells. Stem Cells 29(6):964-71.
  12. Ang YS, Tsai SY, Lee DF, Monk J, Su J, Ratnakumar K, Ding J, Ge Y, Darr H, Chang B, Wang J, Rendl M, Bernstein E, Schaniel C, Lemischka IR. (2011). Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network. Cell 145(2): 183-97.
  13. Tsai SY, Clavel C, Kim S, Ang YS, Grisanti L, Lee DF, Kelley K, Rendl M. (2010). Oct4 and klf4 reprogram dermal papilla cells into induced pluripotent stem cells. Stem Cells 28(2):221-8.
  14. Krick S, Shi S, Ju W, Faul C, Tsai SY, Mundel P, Böttinger EP. (2008). Mpv17l protects against mitochondrial oxidative stress and apoptosis by activation of Omi/HtrA2 protease. Proc. Natl. Acad. Sci. 105(37):14106-11.
  15. Chen CF*, Tsai SY, Ma MC, Wu MS. (2003) Hypoxic preconditioning enhances renal superoxide dismutase levels in rats. J Physiol. 552(Pt 2):561-9.