Our laboratory recently discovered that postnatal human epidermal keratinocytes (KC) could be reprogrammed into a neural crest (NC) fate without genetic introduction of transcription factors or reprogramming to the pluripotent state. The KC-derived NC (KC-NC) could be coaxed to differentiate into all functional NC derivatives including peripheral neurons, melanocytes, Schwann cells and mesenchymal stem cell derivatives (osteocytes, chondrocytes, adipocytes and smooth muscle cells). Upon transplantation into chicken embryos, KC-NC migrated along stereotypical pathways and gave rise to multiple NC derivatives. Here we propose to extend our findings to adult epidermal keratinocytes, provide mechanistic understanding of the NC reprograming process, and demonstrate the use of KC-NC derived Schwann cells for treatment of demyelinating disease.
In aim 1, we will determine whether human adult epidermal keratinocytes can be reprogrammed into neural crest stem cells under defined conditions.
Aim 2 will study the mechanism of KC reprogramming into NC fate.
In aim 3, we will develop a highly efficient strategy to differentiate KC-NC into Schwann cells. The KC-NC Schwann cells will be employed for the treatment of demyelinating disease using a mouse model of congenital hypomyelinating disease that has become the gold standard for the assessment of myelinating cell preparations. This work represents a paradigm shift in stem cell biology as it demonstrates the plasticity of human epidermal cells to be reprogrammed into cells of common developmental origin ? both originate from the ectoderm - without genetic modification and under defined culture conditions. Finally, our work has the potential to provide a novel source of abundant, readily accessible, autologous stem cells for treatment of neurodegenerative diseases, for which cell sourcing remains a severe impediment hampering cell therapy approaches.

Public Health Relevance

We seek to establish the reprogramming potential of adult epidermal keratinocytes into neural crest stem cells and their derivatives including neurons and Schwann cells. Our strategy represents a paradigm shift in stem cell biology because our reprogramming strategy is based on defined culture conditions and does not involve genetic modification or reprogramming to the pluripotent state. The proposed work has enormous implications for regenerative medicine, as it has the potential to provide a novel source of abundant, readily accessible, autologous stem cells for treatment of neurodegenerative diseases, for which cell sourcing remains an intractable barrier to development of cellular therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
1R01EB023114-01
Application #
9196190
Study Section
Special Emphasis Panel (ZRG1-SBIB-V (02)M)
Program Officer
Hunziker, Rosemarie
Project Start
2016-09-14
Project End
2020-06-30
Budget Start
2016-09-14
Budget End
2017-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$463,328
Indirect Cost
$151,467
Name
State University of New York at Buffalo
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
038633251
City
Amherst
State
NY
Country
United States
Zip Code
14228