Apolipoprotein E (ApoE) is a molecular scavenger in the blood and brain with three human isoforms of ApoE (ϵ2, ϵ3, ϵ4) each differentially affecting the function of the protein. ApoE ϵ2 and ϵ3, tend to be protective in the case of atherosclerosis and Alzheimer's disease but ApoE ϵ3 has other disease implications. Therefore, introduction of ApoE ϵ3 may be beneficial. Multipotent mesenchymal stromal cells (MSCs) are adult progenitor cells, which are easily expanded in culture and engraft into host tissues. We tested whether murine MSCs (mMSCs) and human MSCs (hMSCs) from the bone marrow could be used as an expression system to provide ApoE in animal models of atherosclerosis and Alzheimer's disease.
In initial experiments, mMSCs were injected into the lateral ventricles of post-natal ApoE null mice, which constitutively secreted small amounts of ApoE (Peister et al., 2006). The presence of mMSCs resulted in improved cognitive behavioral testing compared to control groups. PCR assays demonstrated that the MSC levels required to elicit the change were extremely low, at the detection limit of the assay.
Un-manipulated hMSCs did not synthesize ApoE mRNA in vitro. Therefore, we examined the potential for induction of expression. A molecular screen revealed that dexamethasone induced and sustained expression of ApoE. The ApoE could bind to lipid, LDLs and the LDL-receptor, demonstrating functionality (Zeitouni et al., 2008).
We next tested the ability of hMSCs to secrete ApoE in the blood, as a strategy for the treatment of severe atherosclerosis. Upon implantation of a fibrin construct containing hMSCs, the cells persisted for one week, causing clear vascularization of the site and high levels of ApoE were secreted into the blood of the mice. Unfortunately, the hMSCs did not survive in immune-competent hosts suggesting an immune-compromised ApoE null mouse is necessary.
The data here demonstrate that administration of MSCs homozygous for ApoE ϵ3 and dexamethasone may represent a novel therapy for ApoE related diseases. Furthermore, MSC conditioned medium may be a future preparation for the administration of human ApoE. These results are therefore a significant step forward for the study and treatment of ApoE related diseases.
|Advisor:||Prockop, Darwin J.|
|Commitee:||Bunnel, Bruce, Deininger, Prescott, Raber, Jacob, Wimley, William|
|School Location:||United States -- Louisiana|
|Source:||DAI-B 70/03, Dissertation Abstracts International|
|Subjects:||Molecular biology, Neurosciences, Cellular biology|
|Keywords:||Alzheimer's disease, Apolipoprotein E, Atherosclerosis, MSCs, Mesenchymal stem cells|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be