Stem cells have tremendous potential in regenerative medicine applications. The generation of induced pluripotent stem cells (iPSCs) bypasses the ethical and immune rejection issues of human embryonic stem cells (hESCs), and provides an unlimited cell source for tissue repair. However, the differentiation and the therapeutic effects of iPSC-derived stem cells have not been well characterized in vitro and in vivo. Here we propose to investigate the differentiation and therapeutic effects of iPSC- derived neural crest stem cells (NCSCs). NCSCs can be derived from ESCs and iPSCs, and can generate many cell types (neural cells, vascular cells, mesenchymal cells, endocrine cells) of all three germ layers, which make it a valuable stem cell source and an ideal model system to study the lineage commitment and therapeutic potential of multipotent stem cells. In addition, nanofibrous biomaterials will be used as scaffolds to deliver stem cells and provide a well-controlled and tissue-specific microenvironment for the investigations of NCSC differentiation and tissue regeneration in vivo. We hypothesize that iPSC-derived NCSC is a valuable cell source for the regeneration of neural, vascular and other tissues and that the differentiation of NCSCs in vivo depends on tissue-specific microenvironment. To test our hypothesis, three Specific Aims are proposed: (1) To derive and characterize NCSCs from iPSCs and ESCs and investigate their differentiation in vitro, (2) To determine the differentiation and therapeutic potential of NCSCs in nanofibrous nerve conduit for peripheral nerve regeneration in vivo, and (3) To determine the differentiation and therapeutic potential of NCSCs in nanofibrous vascular grafts for vascular regeneration in vivo. We will take a multidisciplinary approach and integrate the knowledge and technologies from stem cell biology, biomaterials, tissue engineering, nanotechnology and medicine. The accomplishment of this project will advance our understanding on the differentiation and therapeutic potential of iPSCs and NCSCs, and provide a rational basis for the use of iPSCs and NCSCs, in combination with nanofibrous scaffolds, in the regeneration of neural and vascular tissues. In addition, the research on iPSC-NCSCs will have impact on the therapies for many other diseases such as demyelinating disorders, congenital heart failure, spina bifida, arthritis, osteoporosis and endocrine disorders.

Public Health Relevance

In this project we will explore the differentiation and therapeutic potential of induced pluripotent stem (iPS) cells. The iPS cell-derived multipotent neural crest stem cells will be characterized and combined with nanofibrous scaffolds for peripheral nerve and vascular repair. The accomplishment of this project will break new grounds of using iPS cells for regenerative medicine applications and establish novel technologies and cell sources for therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB012240-04
Application #
8469757
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Hunziker, Rosemarie
Project Start
2010-08-15
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$461,796
Indirect Cost
$156,186
Name
University of California Berkeley
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Sia, Junren; Sun, Raymond; Chu, Julia et al. (2016) Dynamic culture improves cell reprogramming efficiency. Biomaterials 92:36-45
Pu, Juan; Yuan, Falei; Li, Song et al. (2015) Electrospun bilayer fibrous scaffolds for enhanced cell infiltration and vascularization in vivo. Acta Biomater 13:131-41
Sengupta, Debanti; Waldman, Stephen D; Li, Song (2014) From in vitro to in situ tissue engineering. Ann Biomed Eng 42:1537-45
Janairo, Randall Raphael R; Zhu, Yiqian; Chen, Timothy et al. (2014) Mucin covalently bonded to microfibers improves the patency of vascular grafts. Tissue Eng Part A 20:285-93
Cheng, Q; Komvopoulos, K; Li, S (2014) Plasma-assisted heparin conjugation on electrospun poly(L-lactide) fibrous scaffolds. J Biomed Mater Res A 102:1408-14
Li, Song; Sengupta, Debanti; Chien, Shu (2014) Vascular tissue engineering: from in vitro to in situ. Wiley Interdiscip Rev Syst Biol Med 6:61-76
Tang, Zhenyu; Wang, Aijun; Wang, Dong et al. (2013) Smooth muscle cells: to be or not to be? Response to Nguyen et Al. Circ Res 112:23-6
Cheng, Qian; Lee, Benjamin L-P; Komvopoulos, Kyriakos et al. (2013) Engineering the microstructure of electrospun fibrous scaffolds by microtopography. Biomacromolecules 14:1349-60
Downing, Timothy L; Soto, Jennifer; Morez, Constant et al. (2013) Biophysical regulation of epigenetic state and cell reprogramming. Nat Mater 12:1154-62
Lee, Benjamin Li-Ping; Tang, Zhenyu; Wang, Aijun et al. (2013) Synovial stem cells and their responses to the porosity of microfibrous scaffold. Acta Biomater 9:7264-75

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