Defective endothelial progenitor cells (EPCs) may contribute to the progression of coronary artery disease. Defective EPCs and a reduced responsiveness of aged/diseased tissues may also be reasons for the limited success of clinical trials of autologous CD34+ bone marow cels for the treatment of acute myocardial infarction and peripheral artery disease (PAD). In the Preliminary Results section of the proposal we present the first micro!array and micro!RNA (miR) profiles of human CD34+/Lin! EPCs, comparing healthy volunteers with coronary artery disease (CAD) and age!matched non!CAD patients. The results reveal down!regulation of multiple angiogenic, growth and survival factors including VEGF, integrin!1V, Akt, and eNOS in the CAD group, and >3!fold increased expression of miR!92a, a global anti!angiogenesis miR that targets integrin!1V and Akt, miR!16, that targets VEGF and cell cycle genes CCDN!1 and 2, and miR!21 that targets cell migration factors and stem cell self renewal and has also been associated with neointimal formation. Here we will test the hypothesis that ischemia can be effectively and safely resolved on multiple disease backgrounds by tissue engineering with hypoxia!regulated AAV9 vectors expressing pro!angiogenic growth factors, combined with EPC therapy after engineering the EPCs with selective micro!RNAs (premirs) and micro!RNA inhibitors (antagomirs). We have created and tested a series of unique AAV vectors that express pro!angiogenic genes under the direction of hypoxia!regulated, conditionally silenced promoters. When expressing VEGF, these vectors support directional vessel growth, arteriogenesis and stable reperfusion of ischemic hind limbs, and are protective against AMI in a mouse model. The vectors are highly regulated due to the presence of silencer elements that switch off gene expression under physiological oxygen tension. We propose to profile miR expression in different CD34+ and CD133+ cell populations from CAD patients with and without type 2 diabetes and investigate the role of serum factors in regulating miRs expression, and whether normal regulation and function can be recovered pharmacologically. We will determine whether EPC functions can be recovered by molecular genetic engineering of EPCs, and test engineered EPC therapy in multiple models of ischemia on backgrounds of age and atherosclerosis.
In Aims 1 and 2 we will profile miRs, their targets and functions in EPCs from CAD patients 1 T2D and investigate pathways to regain function.
In Aim 3 we will characterize the cellular and molecular events that promote revascularization in response to optimal gene and engineered cell therapy in each model of ischemia and each age/disease background.
Studies are proposed to determine why bone marrow cells from patients with coronary artery disease and peripheral artery disease have defective functions and do not provide efficient therapy when they are collected from a patient's bone marrow, purified and delivered back to the same patient for stem cell therapy. Experiments are proposed to correct the defects in these cells and optimize a cellular bioengineering protocol that will improve stem cell therapy for patients with peripheral and coronary artery disease.
|Zhu, Jinyun; Lu, Kai; Zhang, Ning et al. (2018) Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way. Artif Cells Nanomed Biotechnol 46:1659-1670|
|Shen, Jian; Zhang, Ning; Lin, Yi-Nuo et al. (2018) Regulation of Vascular Calcification by Growth Hormone-Releasing Hormone and Its Agonists. Circ Res 122:1395-1408|
|Wang, Kan; Jiang, Zhi; Webster, Keith A et al. (2017) Enhanced Cardioprotection by Human Endometrium Mesenchymal Stem Cells Driven by Exosomal MicroRNA-21. Stem Cells Transl Med 6:209-222|
|Ma, Qunchao; Xia, Xiangyang; Tao, Quanwei et al. (2016) Profound Actions of an Agonist of Growth Hormone-Releasing Hormone on Angiogenic Therapy by Mesenchymal Stem Cells. Arterioscler Thromb Vasc Biol 36:663-672|
|Adi, Nikhil; Adi, Jennipher; Lassance-Soares, Roberta Marques et al. (2016) High protein/fish oil diet prevents hepatic steatosis in NONcNZO10 mice; association with diet/genetics-regulated micro-RNAs. J Diabetes Metab 7:|
|Hu, Xinyang; Chen, Panpan; Wu, Yan et al. (2016) MiR-211/STAT5A Signaling Modulates Migration of Mesenchymal Stem Cells to Improve its Therapeutic Efficacy. Stem Cells 34:1846-58|
|Hu, Xinyang; Zhang, Ling; Jin, Jing et al. (2015) Heparanase released from mesenchymal stem cells activates integrin beta1/HIF-2alpha/Flk-1 signaling and promotes endothelial cell migration and angiogenesis. Stem Cells 33:1850-1862|
|Thompson, John W; Wei, Jianqin; Appau, Kweku et al. (2015) Bnip3 Binds and Activates p300: Possible Role in Cardiac Transcription and Myocyte Morphology. PLoS One 10:e0136847|
|Graham, Regina M; Thompson, John W; Webster, Keith A (2015) BNIP3 promotes calcium and calpain-dependent cell death. Life Sci 142:26-35|
|Adi, Nikhil; Adi, Jennipher; Cesar, Liliana et al. (2015) Role of Micro RNA-205 in Promoting Visceral Adiposity of NZ10 Mice with Polygenic Susceptibility for Type 2 Diabetes. J Diabetes Metab 6:|
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