Development of Novel Strategies for Cell-based Cardiac Repair

Kiwon BAN 한국생물공학회 2020 한국생물공학회 학술대회 Vol.2020 No.10

In vivo transduction of ETV2 improves cardiac function and induces vascular regeneration following myocardial infarction

Lee, Sunghun,Lee, Dong Hun,Park, Bong-Woo,Kim, Riyoun,Hoang, Anh Duc,Woo, Sang-Keun,Xiong, Wenjun,Lee, Yong Jin,Ban, Kiwon,Park, Hun-Jun Nature Publishing Group UK 2019 Experimental and molecular medicine Vol.51 No.2

<▼1><P>Vascular regeneration in ischemic hearts has been considered a target for new therapeutic strategies. It has been reported that ETV2 is essential for vascular development, injury-induced neovascularization and direct cell reprogramming of non-endothelial cells into endothelial cells. Thus, the objective of this study was to explore the therapeutic potential of ETV2 in murine models of myocardial infarction in vivo. Direct myocardial delivery of lentiviral ETV2 into rodents undergoing myocardial infarction dramatically upregulated the expression of markers for angiogenesis as well as anti-fibrosis and anti-inflammatory factors in vivo. Consistent with these findings, echocardiography showed significantly improved cardiac function in hearts with induced myocardial infarction upon ETV2 injection compared to that in the control virus-injected group as determined by enhanced ejection fraction and fractional shortening. In addition, ETV2-injected hearts were protected against massive fibrosis with a remarkable increase in capillary density. Interestingly, major fractions of capillaries were stained positive for ETV2. In addition, ECs infected with ETV2 showed enhanced proliferation, suggesting a direct role of ETV2 in vascular regeneration in diseased hearts. Furthermore, culture media from ETV2-overexpressing cardiac fibroblasts promoted endothelial cell migration based on scratch assay. Importantly, intramyocardial injection of the adeno-associated virus form of ETV2 into rat hearts with induced myocardial infarction designed for clinical applicability consistently resulted in significant augmentation of cardiac function. We provide compelling evidence that ETV2 has a robust effect on vascular regeneration and enhanced cardiac repair after myocardial infarction, highlighting a potential therapeutic function of ETV2 as an efficient means to treat failing hearts.</P></▼1><▼2><P><B>Cardiovascular disease: New hope for healing the heart</B></P><P>A gene therapy strategy that stimulates cardiovascular repair could improve recovery for heart attack patients. Heart attacks inflict severe damage on the heart and blood vessels, tissues with limited capacity for self-repair. Researchers led by Kiwon Ban of the City University of Hong Kong and Hun-Jun Park of the Catholic University of Korea, Seoul, have now demonstrated that a gene responsible for cardiovascular development can also efficiently stimulate heart repair. They used viruses to deliver the gene into a mouse model of heart attack, and showed that treated heart tissues exhibited strong recovery relative to untreated controls. The treatment reduced scar tissue formation and promoted proliferation of the cells lining blood vessels and blood vessel formation, measurably improving heart function. This approach could lay the groundwork for treating a common potentially fatal event.</P></▼2>

Maturation of Cardiomyocytes Derived from Human Pluripotent Stem Cells: Current Strategies and Limitations

Jiang, Yanqing,Park, Peter,Hong, Sang-Min,Ban, Kiwon Korean Society for Molecular and Cellular Biology 2018 Molecules and cells Vol.41 No.7

The capacity of differentiation of human pluripotent stem cells (hPSCs), which include both embryonic stem cells and induced pluripotent stem cells, into cardiomyocytes (CMs) in vitro provides an unlimited resource for human CMs for a wide range of applications such as cell based cardiac repair, cardiac drug toxicology screening, and human cardiac disease modeling. However, their applicability is significantly limited by immature phenotypes. It has been well known that currently available CMs derived from hPSCs (hPSC-CMs) represent immature embryonic or fetal stage CMs and are functionally and structurally different from mature human CMs. To overcome this critical issue, several new approaches aiming to generate more mature hPSC-CMs have been developed. This review describes recent approaches to generate more mature hPSC-CMs including their scientific principles, advantages, and limitations.

Maturation of Cardiomyocytes Derived from Human Pluripotent Stem Cells: Current Strategies and Limitations

Yanqing Jiang,Peter Park,홍상민,Kiwon Ban 한국분자세포생물학회 2018 Molecules and cells Vol.41 No.7

The capacity of differentiation of human pluripotent stem cells (hPSCs), which include both embryonic stem cells and induced pluripotent stem cells, into cardiomyocytes (CMs) in vitro provides an unlimited resource for human CMs for a wide range of applications such as cell based cardiac repair, cardiac drug toxicology screening, and human cardiac disease modeling. However, their applicability is significantly limited by immature phenotypes. It has been well known that currently available CMs derived from hPSCs (hPSC-CMs) represent immature embryonic or fetal stage CMs and are functionally and structurally different from mature human CMs. To overcome this critical issue, several new approaches aiming to generate more mature hPSC-CMs have been developed. This re-view describes recent approaches to generate more mature hPSC-CMs including their scientific prin-ciples, advantages, and limitations.

Challenges and Limitations of Strategies to Promote Therapeutic Potential of Human Mesenchymal Stem Cells for Cell-Based Cardiac Repair

Thi Van Anh Bui,Ji-Won Hwang,Jung-Hoon Lee,Hun-Jun Park,Kiwon Ban 대한심장학회 2021 Korean Circulation Journal Vol.51 No.2

Mesenchymal stem cells (MSCs) represent a population of adult stem cells residing in many tissues, mainly bone marrow, adipose tissue, and umbilical cord. Due to the safety and availability of standard procedures and protocols for isolation, culturing, and characterization of these cells, MSCs have emerged as one of the most promising sources for cell-based cardiac regenerative therapy. Once transplanted into a damaged heart, MSCs release paracrine factors that nurture the injured area, prevent further adverse cardiac remodeling, and mediate tissue repair along with vasculature. Numerous preclinical studies applying MSCs have provided significant benefits following myocardial infarction. Despite promising results from preclinical studies using animal models, MSCs are not up to the mark for human clinical trials. As a result, various approaches have been considered to promote the therapeutic potency of MSCs, such as genetic engineering, physical treatments, growth factor, and pharmacological agents. Each strategy has targeted one or multi-potentials of MSCs. In this review, we will describe diverse approaches that have been developed to promote the therapeutic potential of MSCs for cardiac regenerative therapy. Particularly, we will discuss major characteristics of individual strategy to enhance therapeutic efficacy of MSCs including scientific principles, advantages, limitations, and improving factors. This article also will briefly introduce recent novel approaches that MSCs enhanced therapeutic potentials of other cells for cardiac repair.

Vascular regeneration and skeletal muscle repair induced by long-term exposure to SDF-1α derived from engineered mesenchymal stem cells after hindlimb ischemia

Kim Jin-Ju,Park Jae-Hyun,Kim Hyeok,Sim Woo-Sup,Hong Seokbeom,Choi Yeon-Jik,Kim Hyo-Jin,Lee Soon Min,Kim Dongha,Kang Sun-woong,Ban Kiwon,Park Hun-Jun 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-

Despite recent progress in medical and endovascular therapy, the prognosis for patients with critical limb ischemia (CLI) remains poor. In response, various stem cells and growth factors have been assessed for use in therapeutic neovascularization and limb salvage in CLI patients. However, the clinical outcomes of cell-based therapeutic angiogenesis have not provided the promised benefits, reinforcing the need for novel cell-based therapeutic angiogenic strategies to cure untreatable CLI. In the present study, we investigated genetically engineered mesenchymal stem cells (MSCs) derived from human bone marrow that continuously secrete stromal-derived factor-1α (SDF1α-eMSCs) and demonstrated that intramuscular injection of SDF1α-eMSCs can provide long-term paracrine effects in limb ischemia and effectively contribute to vascular regeneration as well as skeletal muscle repair through increased phosphorylation of ERK and Akt within the SDF1α/CXCR4 axis. These results provide compelling evidence that genetically engineered MSCs with SDF-1α can be an effective strategy for successful limb salvage in limb ischemia.

CU06-1004 enhances vascular integrity and improves cardiac remodeling by suppressing edema and inflammation in myocardial ischemia–reperfusion injury

Zhang Haiying,Kim Hyeok,Park Bong Woo,Noh Minyoung,Kim Yeomyeong,Park Jeongeun,Park Jae-Hyun,Kim Jin-Ju,Sim Woo-Sup,Ban Kiwon,Park Hun-Jun,Kwon Young-Guen 생화학분자생물학회 2022 Experimental and molecular medicine Vol.54 No.-

Ischemia–reperfusion (I/R) injury accelerates the cardiomyocytes (CMs) death by oxidative stress, and thereby deteriorates cardiac function. There has been a paradigm shift in the therapeutic perspective more towards the prevention or amelioration of damage caused by reperfusion. Cardiac microvascular endothelial cells (CMECs) are more vulnerable to reperfusion injury and play the crucial roles more than CMs in the pathological process of early I/R injury. In this study, we investigate that CU06-1004, as a vascular leakage blocker, can improve cardiac function by inhibiting CMEC’s hyperpermeability and subsequently reducing the neutrophil’s plugging and infiltration in infarcted hearts. CU06-1004 was delivered intravenously 5 min before reperfusion and the rats were randomly divided into three groups: (1) vehicle, (2) low-CU06-1004 (1 mg/kg, twice at 24 h intervals), and (3) high-CU06-1004 (5 mg/kg, once before reperfusion). CU06-1004 treatment reduced necrotic size and cardiac edema by enhancing vascular integrity, as demonstrated by the presence of intact junction proteins on CMECs and surrounding pericytes in early I/R injury. It also decreased the expression of vascular cell adhesion molecule 1 (VCAM-1) on CMECs, resulting in reduced infiltration of neutrophils and macrophages. Echocardiography showed that the CU06-1004 treatment significantly improved cardiac function compared with the vehicle group. Interestingly, single high-dose treatment with CU06-1004 provided a greater functional improvement than repetitive low-dose treatment until 8 weeks post I/R. These findings demonstrate that CU06-1004 enhances vascular integrity and improves cardiac function by preventing lethal myocardial I/R injury. It can provide a promising therapeutic option, as potential adjunctive therapy to current reperfusion strategies.