The Studer lab has pioneered directed differentiation of pluripotent stem cells towards CNS and PNS fates. Early contributions include the first example of a neuron subtype-specific differentiation protocol from hESCs1 the isolation of hESC-derived neural stem cells of both CNS-2, 3 and PNS-4 identity, the development of BAC transgenesis and the first HTS-based chemical screens in hESCs5.
We have also made key contributions to the human iPSC-field including our work on familial dysautonomia6, considered a landmark paper in human disease modeling. We further defined prospective markers to assess neural differentiation propensity of hESC/hiPSC lines7 and developed strategies for unbiased miRNA target identification in hESCs8.
A particular focus in the lab is directed differentiation based on our highly efficient and defined neural induction protocol ("dual-SMAD-inhibition")9 which offers a modular approach for generating most major CNS and PNS cell types9-11. We also described a combinatorial small molecule approach to trigger ultra-rapid neuronal induction and to yield enriched populations of functional nociceptors12. Finally, we have demonstrated the derivation of authentic midbrain dopamine neurons from human ESC and iPSC lines with long-term in vivo survival and functional data across three PD models (mouse, rat, rhesus monkey)11. Those studies led to a NYSTEM funded consortium grant with the goal of developing a clinical grade source of human ESC derived dopamine neurons for cell replacement trials in PD patients.
1.Perrier et al., PNAS 101,12543-8(2004); Elkabetz et al., 2.G&D. 22,152-165(2008); 3.Tabar et al., Nat.Biotechnol. 23,601-606(2005).; 4.Lee et al., Nat.Biotechnol. 25,1468-1475(2007); 5.Desbordes et al., Cell Stem Cell 2,602-612(2008); 6. Lee et al., Nature 461,402-406(2009); 7.Kim et al., Cell Stem Cell 8,695-706(2011); 8.Lipchina et al., G&D. 25,2173-2186(2011); 9.Chambers et al., Nat.Biotechnol. 27(3)275-280(2009); 10.Fasano et al., Cell Stem Cell 6,336-347(2010); 11. Kriks et al., Nature 480,547-551(2011); 12.Chambers et al., Nat.Biotechnol. 30(7):715-20 (2012)
Ganat YM, Calder EL, Kriks S, Nelander J, Tu EY, Jia F, Battista D, Harrison N, Parmar M, Tomishima MJ, Rutishauser U, Studer L. Identification of embryonic stem cell-derived midbrain dopaminergic neurons for engraftment. J Clin Invest. 2012 Jul 2. pii: 58767. doi: 10.1172/JCI58767.
Chambers SM, Qi Y, Mica Y, Lee G, Zhang XJ, Niu L, Bilsland J, Cao L, Stevens E, Whiting P, Shi SH, Studer L. Combined small-molecule inhibition accelerates developmental timing and converts human pluripotent stem cells into nociceptors. Nat Biotechnol. 2012 Jul 1. doi: 10.1038/nbt.2249
Lipchina I, Elkabetz Y, Hafner M, Sheridan R, Mihailovic A, Tuschl T, Sander C,Studer L, Betel D. Genome-wide identification of microRNA targets in human ES cells reveals a role for miR-302 in modulating BMP response. Genes Dev. 2011 Oct 15;25(20):2173-86. doi: 10.1101/gad.17221311.
Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, Carrillo-Reid L, Auyeung G, Antonacci C, Buch A, Yang L, Beal MF, Surmeier DJ, Kordower JH, Tabar V, Studer L. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature. 2011 Nov 6;480(7378):547-51. doi: 10.1038/nature10648.
Kim H, Lee G, Ganat Y, Papapetrou EP, Lipchina I, Socci ND, Sadelain M, Studer L. miR-371-3 expression predicts neural differentiation propensity in human pluripotent stem cells. Cell Stem Cell. 2011 Jun 3;8(6):695-706.
Fasano CA, Chambers SM, Lee G, Tomishima MJ, Studer L. Efficient derivation of functional floor plate tissue from human embryonic stem cells. Cell Stem Cell. 2010 Apr 2;6(4):336-47.
Lee GS, Papapetrou EP, Kim HS, Chambers SM, Tomishima MJ, Fasano CA, Ganat Y, Menon J, Shimizu F, Viale A, Tabar V, Sadelain M, Studer L. (2009) Modeling pathogenesis and treatment of Familial Dysautonomia in patient specific iPS cells. Nature. 2009 Sep 17;461(7262):402-6. Epub 2009 Aug 19.
Papapetrou EP, Tomishima MJ, Chambers SM, Mica Y, Reed E, Menon J, Tabar V, Mo Q, Studer L, Sadelain M. (2009). Stoichiometric and temporal requirements of Oct4, Sox2, Klf4, and c-Myc expression for efficient human iPSC induction and differentiation. Proc Natl Acad Sci U S A. 2009 Jun 23. [Epub ahead of print]
Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L. (2009). Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 27(3):275-80
Fasano CA, Phoenix TN, Kokovay E, Lowry N, Elkabetz Y, Dimos JT, Lemischka IR, Studer L, Temple S. (2009) Bmi-1 cooperates with Foxg1 to maintain neural stem cell self-renewal in the forebrain. Genes Dev. 2009;23(5):561-74.
Desbordes SC, Placantonakis DG, Ciro A, Socci ND, Lee G, Djaballah H, Studer L. (2008) High-throughput screening assay for the identification of compounds regulating self-renewal and differentiation in human embryonic stem cells. Cell Stem Cell. 2(6):602-12.
Tabar V, Tomishima M+, Panagiotakos G+, Wakayama S, Menon J, Mizutani E, AlShamy G, Ohta H, Wakayama T, Studer, L. (2008) Therapeutic cloning in individual Parkinsonian mice. Nature Medicine 2008 Apr;14(4):379-81.
Elkabetz Y, Panagiotakos G, Al Shamy G, Socci ND, Tabar V, Studer LHuman ES cell-derived neural rosettes reveal a functionally distinct early neural stem cell stage. Genes Dev. (Cover article) 2008 Jan 15;22(2):152-65.