Diabetes, Parkinson's, Alzheimer's, Huntington's, heart disease, muscular dystrophy and osteoarthritis are some of degenerative diseases that would benefit from cell transplantation. However, the benefits of cell transplantation will not be fully realized unless customized, patient- specific cells become available. Current cell-based therapies that are being developed from human embryonic stem cells and adult stem cells would require life-long immuno-suppression in the majority of patients. Cells and tissues customized to the needs of a specific patient are not available and there are no published reports on the derivation of therapeutically useful cells from patient's own differentiated tissue. Only vertebrate eggs contain the biochemical machinery that has the ability to erase adult cell nuclear memory and replace it with the lost embryonic nuclear memory (de-differentiation), as demonstrated by animal cloning successes in several animal species. The objectives of the proposal are to de-differentiate human adult skin fibroblasts into stem-like cells using Xenopus egg extract, identify and characterize Xenopus egg extract components that are required for de-differentiation and validate the therapeutic utility of stem- like cells by inducing tumor formation in SCID mice. The project will develop stem-like de-differentiated cells from adult human fibroblasts with Xenopus egg extract;we will identify and characterized extract components required for de-differentiation and test stem-like cells for their developmental potential. De-differentiated cells can then be used to develop novel therapeutic, patient-specific (autologous) cells for cell therapy of degenerative diseases.

Public Health Relevance

The project will develop stem-like de-differentiated cells from adult human fibroblasts with Xenopus egg extract;we will identify and characterized extract components required for de-differentiation and test stem-like cells for their developmental potential. De-differentiated cells can then be used to develop novel therapeutic, patient-specific (autologous) cells for cell therapy of degenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM085456-02S2
Application #
7905632
Study Section
Special Emphasis Panel (ZGM1-GDB-7 (EU))
Program Officer
Haynes, Susan R
Project Start
2008-08-01
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
2
Fiscal Year
2009
Total Cost
$104,069
Indirect Cost
Name
Worcester Polytechnic Institute
Department
Biology
Type
Schools of Engineering
DUNS #
041508581
City
Worcester
State
MA
Country
United States
Zip Code
01609
Dolivo, David M; Larson, Sara A; Dominko, Tanja (2018) Tryptophan metabolites kynurenine and serotonin regulate fibroblast activation and fibrosis. Cell Mol Life Sci 75:3663-3681
Dolivo, David M; Larson, Sara A; Dominko, Tanja (2017) Fibroblast Growth Factor 2 as an Antifibrotic: Antagonism of Myofibroblast Differentiation and Suppression of Pro-Fibrotic Gene Expression. Cytokine Growth Factor Rev 38:49-58
Dolivo, David M; Larson, Sara A; Dominko, Tanja (2017) FGF2-mediated attenuation of myofibroblast activation is modulated by distinct MAPK signaling pathways in human dermal fibroblasts. J Dermatol Sci 88:339-348
Kole, Denis; Grella, Alexandra; Dolivo, David et al. (2017) High molecular weight FGF2 isoforms demonstrate canonical receptor-mediated activity and support human embryonic stem cell self-renewal. Stem Cell Res 21:106-116
Hernandez, Sarah J; Dolivo, David M; Dominko, Tanja (2017) PRMT8 demonstrates variant-specific expression in cancer cells and correlates with patient survival in breast, ovarian and gastric cancer. Oncol Lett 13:1983-1989
Grella, Alexandra; Kole, Denis; Holmes, William et al. (2016) FGF2 Overrides TGF?1-Driven Integrin ITGA11 Expression in Human Dermal Fibroblasts. J Cell Biochem 117:1000-8
Hernandez, Sarah; Dominko, Tanja (2016) Novel Protein Arginine Methyltransferase 8 Isoform Is Essential for Cell Proliferation. J Cell Biochem 117:2056-66
Jez, Mojca; Ambady, Sakthikumar; Kashpur, Olga et al. (2014) Expression and differentiation between OCT4A and its Pseudogenes in human ESCs and differentiated adult somatic cells. PLoS One 9:e89546
Kole, Denis; Ambady, Sakthikumar; Page, Raymond L et al. (2014) Maintenance of multipotency in human dermal fibroblasts treated with Xenopus laevis egg extract requires exogenous fibroblast growth factor-2. Cell Reprogram 16:18-28
Kashpur, Olga; LaPointe, David; Ambady, Sakthikumar et al. (2013) FGF2-induced effects on transcriptome associated with regeneration competence in adult human fibroblasts. BMC Genomics 14:656

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