Induced pluripotent stem (iPS) cells have enormous potential for the repair of diseased or traumatized blood vessels. Indeed, we, among the first, have successfully induced iPS cell differentiation to smooth muscle cells (SMC) using all-trans retinoid acid (atRA). Our long-term goal is to regenerate functional human blood vessels using patient-derived iPS cells. The key to a functional blood vessel regeneration using iPS cells is the differentiation and maintenance of the contractile phenotype of the vascular SMC. The overall hypothesis is that the coordination of the key signaling molecules with the biomimetic microenvironment defined by an advanced scaffold is required for achieving the contractile phenotype of iPS-derived vascular SMC and functional blood vessel regeneration. The Hippo-YAP signaling pathway has recently been found to play a critical role in maintaining iPS cell pluoripotency. Supported by preliminary data, we hypothesize that Yap1 is a critical molecule inhibiting the differentiation of iPS cells to vascular SMC and suppressing the contractile phenotype of vascular SMC. We developed 3D porous and nanofibrous (NF) scaffolds and found that the NF architecture enhanced iPS cell differentiation to vascular SMC and the contractile phenotype over control scaffolds. In this project, we will first define the role of Yap in regulating iPS cell differentiation to vascular SMC and vascular SMC phenotypic switch in a 2D culture system. We will then develop optimal NF scaffolds to define the role of Yap1 in regulating iPS cell differentiation to vascular SMC in 3D culture system. We will also develop controlled release system inside the scaffolds to maximize the utility of atRA along with Yap1 modulation in enhancing the vascular SMC differentiation and their mature contractile phenotype maintenance. Built on these mechanistic understandings and advanced technologies, we will engineer blood vessels and evaluate them using bioreactors and a rat implantation model. By accomplishing these specific aims, we will improve mechanistic understandings of iPS cell differentiation to vascular SMC and develop key technologies to advance the therapeutic utility of patient based iPS cells for human vascular regeneration.
Regenerating Blood Vessels using iPS Cells Cardiovascular disease (CVD) is the most common cause of death in the United States. There are significant limitations of the current practice of replacing/repairing defective and diseased vascular tissues because of limited availability of suitable vessels from the patients and serious drawbacks of synthetic grafts. Recently, induced pluripotent stem (iPS) cell techniques provide a way to generate individualized cell lines from a patient's own tissue, and show promising therapeutic potential. In this project, we will conduct mechanistic studies and develop advanced bioengineering technologies to enhance the blood vessel regeneration using iPS cells through a synergistic multidisciplinary approach.
|Hei, Mingyang; Wang, Jun; Wang, Kelly et al. (2017) Dually responsive mesoporous silica nanoparticles regulated by upper critical solution temperature polymers for intracellular drug delivery. J Mater Chem B 5:9497-9501|
|Zhang, Zhanpeng; Eyster, Thomas W; Ma, Peter X (2016) Nanostructured injectable cell microcarriers for tissue regeneration. Nanomedicine (Lond) 11:1611-28|
|Niu, Xufeng; Liu, Zhongning; Hu, Jiang et al. (2016) Microspheres Assembled from Chitosan-Graft-Poly(lactic acid) Micelle-Like Core-Shell Nanospheres for Distinctly Controlled Release of Hydrophobic and Hydrophilic Biomolecules. Macromol Biosci 16:1039-47|
|Kuang, Rong; Zhang, Zhanpeng; Jin, Xiaobing et al. (2016) Nanofibrous spongy microspheres for the delivery of hypoxia-primed human dental pulp stem cells to regenerate vascularized dental pulp. Acta Biomater 33:225-34|
|Zhang, Xiaojin; Li, Yan; Chen, Y Eugene et al. (2016) Cell-free 3D scaffold with two-stage delivery of miRNA-26a to regenerate critical-sized bone defects. Nat Commun 7:10376|
|Wang, Lunchang; Hu, Jiang; Sorek, Claire E et al. (2016) Fabrication of tissue-engineered vascular grafts with stem cells and stem cell-derived vascular cells. Expert Opin Biol Ther 16:317-30|
|Rambhia, Kunal J; Ma, Peter X (2015) Controlled drug release for tissue engineering. J Control Release 219:119-128|
|Hou, Sen; Wang, Xuefei; Park, Sean et al. (2015) Rapid Self-Integrating, Injectable Hydrogel for Tissue Complex Regeneration. Adv Healthc Mater 4:1491-5, 1423|
|Tian, Shuo; Liu, Qihai; Gnatovskiy, Leonid et al. (2015) Heart Regeneration with Embryonic Cardiac Progenitor Cells and Cardiac Tissue Engineering. J Stem Cell Transplant Biol 1:|
|Fan, Jianglin; Kitajima, Shuji; Watanabe, Teruo et al. (2015) Rabbit models for the study of human atherosclerosis: from pathophysiological mechanisms to translational medicine. Pharmacol Ther 146:104-19|
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