Our laboratory aims at exploiting recent advances in stem cell biology to develop radically new therapies for degenerative disease and cancer. We work with both embryonic and adult stem cell types in the lab. However, the main current focus is on the biology and use of human embryonic stem cells. Embryonic stem cells may provide a truly unlimited source for deriving therapeutically relevant cell types. In the mouse, studies have demonstrated that embryonic stem cells can give rise to virtually any cell type present in the adult organism.
Midbrain Dopamine and Spinal Motoneurons from human ES cells
Human ES derived midbrain dopamine neurons co-express tyrosine-hydroxylase and engrailed (left panel), while motoneurons express HB9 and Tuj1 (righ panel)
A major effort of the lab is devoted to harnessing and manipulating the differentiation potential of embryonic stem cells. The efficient generation of specific brain cell populations in vitro, such as dopamine, GABA, motor neurons, or myelinating oligodendrocytes, can serve as a potential cellular source for brain repair in Parkinson's Disease, Huntington's Disease, ALS (Lou Gehrig's Disease), and demyelinating conditions. We are also interested in applications outside the CNS particularly in musculoskeletal disease. Probing the molecular signals required for converting stem cells into specialized cell types in a culture dish will also provide novel insights into basic mechanisms of development. The lab is developing high throughput chemical and genetic screens to systematically address such questions in human embryonic stem cells.
We have recently succeeded in converting mouse and human embryonic stem cells into specific types of brain cells. This technology can combine the power of mouse genetics with defined in vitro assays of neural development. Manipulation of the embryonic stem cell genome to carry dominant and recessive mutations is the basis for the current revolution in mammalian genetics. Our techniques will allow dissection of the specific function of such mutations in brain development, including mutations that would lead to an early embryonic death during in vivo development. Study of developmental processes in a culture dish will also provide a platform for developing high-throughput functional genomic approaches.
Novel protocols in the lab allow the isolation of multipotent mesenchymal precursors from human embryonic stem cells. Such human embryonic stem cell derived mesenchymal precursors can be expanded in vitro or differentiated into fat, cartilage, bone and skeletal muscle cells. We are currently assessing the therapeutic potential of human stem cell derived mesenchymal precursors in musculoskeletal disease.
Autologous dopamine neurons can be generated from the tail cells of an adult mouse by combining nuclear transfer and stem cell technologies.
Cell therapy raises the issue of immunocompatibility between transplanted cells and recipient. An ideal cell source would contain DNA that matches that of a potential patient. In animal models, we are developing 3 distinct strategies toward this goal:
1) Nuclear reprogramming (via nuclear transfer into an oocyte) allows the generation of mouse embryonic stem cell lines from adult somatic cells. In a collaborative effort, we have produced a large number of such lines from adult somatic cells. We have shown that such ntES cells can be coaxed into many specialized cell types, including midbrain dopamine neurons.
We have also demonstrated the function of ntES derived dopamine neurons in vivo upon transplantation into a mouse model of Parkinson's Disease (see Memorial Sloan-Kettering press release.
2) Parthenogenesis allows the generation of pluripotent ES-like stem cells via activation of an unfertilized egg. In a collaborative effort, our lab has demonstrated the derivation and differentiation of parthenogenetic stem from an adult monkey into a variety of specoalized cell types.
For additional information see our Science Brevia article [PubMed Abstract].
3) Future research will be directed toward identifying the molecules responsible for the reprograming of adult cells (e.g., during nuclear transfer). Such molecules could be used to reprogram adult cells directly without the need for nuclear transfer.
Confocal picture of dopaminergic neurons (green) generated in vitro from proliferating brain stem cells, as evidenced by BrdU incorporation (red).
We have described how midbrain rat stem cells and human brain stem cells can be proliferated in culture and differentiated into dopamine neurons that, upon transplantation, restore behavioral deficits in a rat model of Parkinson's Disease. Studies directed toward the clinical application of CNS stem cells in Parkinson's Disease are underway.
Additional ongoing studies demonstrate that similar techniques allow the successful derivation of GABA neurons from brain stem cells with subsequent transplantation into animal models of Huntington's Disease.
We have recently optimized techniques for hESC growth and differentiation under conditions suitable for high throughput chemical and genetic screens. Such technology will allow the identification of specific chemicals and genes that influence stem cell differentiation. This work is done in collaboration with the SKI High Throughput Screening core facility, headed by Hakim Djaballah.
Recent funding from www.projectals.org and the www.alsa.org opens up new opportunities to explore the use of human embryonic stem cells in the treatment of ALS.
Recent Support from the Kinetics Foundation has been essential in studies comparing the potential of various hES cell lines for the future treatment of Parkinson's disease. Currently over 20 hESC lines are being tested.
New funding from the Starr Foundation will allow the Studer lab to expand current efforts and to explore novel uses of embryonic stem cells in animal models of disease. The new Tri-Institutional Stem Cell Initiative will also create new Core-Facilities for Human Embryonic Stem Cell Research that should greatly accelerate the efforts in the lab.
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.
Lee G, Papapetrou EP, Kim H, Chambers SM, Tomishima MJ, Fasano CA, Ganat YM, Menon J, Shimizu F, Viale A, Tabar V, Sadelain M, Studer L. Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature. 2009 Sep 17;461(7262):402-6. doi: 10.1038/nature08320. Epub 2009 Aug 19.
Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009 Mar;27(3):275-80. doi: 10.1038/nbt.1529. Epub 2009 Mar 1.
Lee G, Ramirez CN, Kim H, Zeltner N, Liu B, Radu C, Bhinder B, Kim YJ, Choi IY, Mukherjee-Clavin B, Djaballah H, Studer L. Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression. Nat Biotechnol. 2012 Dec;30(12):1244-8. doi: 10.1038/nbt.2435. Epub 2012 Nov 25.
Lafaille FG, Pessach IM, Zhang SY, Ciancanelli MJ, Herman M, Abhyankar A, Ying SW, Keros S, Goldstein PA, Mostoslavsky G, Ordovas-Montanes J, Jouanguy E, Plancoulaine S, Tu E, Elkabetz Y, Al-Muhsen S, Tardieu M, Schlaeger TM, Daley GQ, Abel L, Casanova JL, Studer L, Notarangelo LD. Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells. Nature. 2012 Nov 29;491(7426):769-73. doi: 10.1038/nature11583. Epub 2012 Oct 28.
Annemarie Opprecht Parkinson Award, Annemarie Opprecht Foundation (2012)
Louise and Allston Boyer Young Investigator in Basic Research, Memorial Sloan-Kettering Cancer Center (2005)
Lorenz Studer is excited by the power that embryonic stem cells hold for treating disease as well as repairing damage caused by cancer therapy.
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