Pharmaceutical induction of ApoE secretion by multipotent mesenchymal stromal cells (MSCs).
BACKGROUND
Apolipoprotein E (ApoE) is a molecular scavenger in the blood and brain. Aberrant function of the molecule causes formation of protein and lipid deposits or "plaques" that characterize Alzheimer's disease (AD) and atherosclerosis. There are three human isoforms of ApoE designated epsilon2, epsilon3, and epsilon4. Each isoform differentially affects the structure and function of the protein and thus the development of disease. Homozygosity for ApoE epsilon4 is associated with atherosclerosis and Alzheimer's disease whereas ApoE epsilon2 and epsilon3 tend to be protective. Furthermore, the epsilon2 form may cause forms of hyperlipoproteinemia. Therefore, introduction of ApoE epsilon3 may be beneficial to patients that are susceptible to or suffering from these diseases. Mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) are adult progenitor cells found in numerous tissues. They are easily expanded in culture and engraft into host tissues when administered appropriately. Furthermore, MSCs are immunosuppressive and have been reported to engraft as allogeneic transplants. In our previous study, mouse MSCs (mMSCs) were implanted into the brains of ApoE null mice, resulting in production of small amounts of ApoE in the brain and attenuation of cognitive deficits. Therefore human MSCs (hMSCs) are a promising vector for the administration of ApoE epsilon3 in humans.


RESULTS
Unlike mMSCs, hMSCs were found not to express ApoE in culture; therefore a molecular screen was performed for compounds that induce expression. PPARgamma agonists, neural stem cell conditioned medium, osteo-inductive media, dexamethasone, and adipo-inductive media (AIM) were tested. Of the conditions tested, only AIM or dexamethasone induced sustained secretion of ApoE in MSCs and the duration of secretion was only limited by the length of time MSCs could be sustained in culture. Upon withdrawal of the inductive stimuli, the ApoE secretion persisted for a further 14 days.


CONCLUSIONS
The data demonstrated that pre-treatment and perhaps co-administration of MSCs homozygous for ApoE epsilon3 and dexamethasone may represent a novel therapy for severe instances of AD, atherosclerosis and other ApoE-related diseases.
Zeitouni
Suzanne
S
Center for Gene Therapy, Tulane University Medical School, New Orleans, LA, 70115, USA. szeitoun@tulane.edu
Ford
Brian S
BS
Harris
Sean M
SM
Whitney
Mandolin J
MJ
Gregory
Carl A
CA
Prockop
Darwin J
DJ
D000544:Alzheimer Disease / Q000628:therapy; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000378:metabolism*; D050197:Atherosclerosis / Q000628:therapy; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007700:Kinetics; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D039902:Multipotent Stem Cells / Q000378:metabolism; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D017077:Culture Media, Conditioned; D003907:Dexamethasone