In our previous study, human neural stem cells (HNSCs), proliferated in vitro for more than a year and transplanted into 24-month-old rat brains, migrated and differentiated into neural cells, and significantly improved the cognitive functions of these animals. Although HNSCs are a valuable source of transplantable material as an alternative to fetal neural tissue, the ideal replacement therapies would be the autologous transplantation. Since we have succeeded in producing neural cells from human mesenchymal stem cells (HMeSCs}, we propose the use of HMeSC for neuroreplacement therapies. Our long-range goal is to identify the regulation of the mechanisms of stem cell lineage and to establish neuroreplacement therapy using HMeSCs isolated from individual patients. The central hypothesis of this application is that HMeSCs treated with bromodeoxyuridin (BrdU) produce neural cells that are functionally similar to HNSC-derived cells. The objectives of this project are to find clues for the regulation of mechanisms for stem cell lineage, and to collect basic data for optimal neuroreplacement therapies using HMeSCs.
Aim 1. Investigation of the effects of BrdU on neural differentiation of MeSCs.
Aim 2. Time-course assessment of HMeSC migration and differentiation after transplantation into the adult brain.
Aim 3. To investigate whether MeSC transplantation improves the cognitive functions of aged memory-impaired rats.
Aim 4. To investigate whether there is a specific temporal window for efficient neuroreplacement by MeSCs in an Alzheimer's disease lesion model. The proposed research is innovative, because it focuses on the ability of a biological function; i.e., the use of BrdU, to change the lineage of MeSCs, which may facilitate autologous transplantation in neuroreplacement strategies. This proposal is expected to have the following outcomes: (1) a demonstration that BrdU treatment alters HMeSC lineage to produce neural cells in vitro by DNA methylation modification; (2) a demonstration that BrdU-treated HMeSCs differentiate and migrate into their proper position in the adult brain after i.c.v, transplantation; (3) a recovery of cognitive function by HMeSC transplantation in an aged animal model; and (4) a replacement of neurons in an Alzheimer's disease lesion model. The proposed research is expected to provide fundamental data to develop clinical applications for MeSCs transplantation in patients with neurodegenerative diseases through autologus transplantation. Thus, the proposed studies are expected to make a breakthrough in therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG023472-01
Application #
6603525
Study Section
Special Emphasis Panel (ZHL1-CSR-J (F2))
Program Officer
Wise, Bradley C
Project Start
2003-06-15
Project End
2008-05-31
Budget Start
2003-06-15
Budget End
2004-05-31
Support Year
1
Fiscal Year
2003
Total Cost
$272,773
Indirect Cost
Name
University of Illinois at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Kwak, Young-Don; Hendrix, Brandon J; Sugaya, Kiminobu (2014) Secreted type of amyloid precursor protein induces glial differentiation by stimulating the BMP/Smad signaling pathway. Biochem Biophys Res Commun 447:394-9
Kwak, Young-Don; Marutle, Amelia; Dantuma, Elise et al. (2011) Involvement of notch signaling pathway in amyloid precursor protein induced glial differentiation. Eur J Pharmacol 650:18-27
Kwak, Young-Don; Dantuma, Elise; Merchant, Stephanie et al. (2010) Amyloid-? precursor protein induces glial differentiation of neural progenitor cells by activation of the IL-6/gp130 signaling pathway. Neurotox Res 18:328-38
Vrotsos, Emmanuel George; Kolattukudy, Pappachan E; Sugaya, Kiminobu (2009) MCP-1 involvement in glial differentiation of neuroprogenitor cells through APP signaling. Brain Res Bull 79:97-103
Keilani, Serene; Sugaya, Kiminobu (2008) Reelin induces a radial glial phenotype in human neural progenitor cells by activation of Notch-1. BMC Dev Biol 8:69
Sugaya, Kiminobu; Merchant, Stephanie (2008) How to approach Alzheimer's disease therapy using stem cell technologies. J Alzheimers Dis 15:241-54
Sugaya, K; Kwak, Y D; Ohmitsu, O et al. (2007) Practical issues in stem cell therapy for Alzheimer's disease. Curr Alzheimer Res 4:370-7
Pulido, Jose S; Sugaya, Ikuko; Comstock, Jordan et al. (2007) Reelin expression is upregulated following ocular tissue injury. Graefes Arch Clin Exp Ophthalmol 245:889-93
Marutle, Amelia; Ohmitsu, Masao; Nilbratt, Mats et al. (2007) Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine. Proc Natl Acad Sci U S A 104:12506-11
Sugaya, Ikuko; Qu, Tingyu; Sugaya, Kiminobu et al. (2006) Genetically engineered human mesenchymal stem cells produce met-enkephalin at augmented higher levels in vitro. Cell Transplant 15:225-30

Showing the most recent 10 out of 14 publications