In separate experiments, antibody-induced reduction in NK cells led to the same beneficial myocardial effects, demonstrating the itMSC-induced NK cell decrease plays a causal role in the observed beneficial myocardial effects produced by itMSCs.
"Since itMSCs secrete factors that have marked anti-inflammatory effects, we designed a study to determine if intravenously administered itMSCs can improve cardiac function following an AMI and, if so, whether such improvement is partially mediated by systemic anti-inflammatory activities," says Dr. Stephen Epstein, Director, Translational and Vascular Biology Research at MedStar Heart and Vascular Institute. "The study impressively demonstrates the validity of these concepts. IV itMSC administration indeed improves cardiac function, and the itMSCs achieve this – at least, in part, – by their anti-inflammatory effects and abilities to decrease NK cells. These findings can profoundly impact future strategies for treating patients with AMI."
Here is a summary of the methodology and results:
- Methodology: CD1 male mice underwent 45 minutes of left anterior descending artery occlusion. Tail-vein injection of human itMSCs grown chronically at 5% O2 was performed 24 hours following MI. itMSCs were labeled with indium-111 oxine. Each animal was injected with 1x106 cells, and ex vivo phosphor imaging of the heart was performed 24 hours following itMSC injection. In a separate study, mice underwent baseline echocardiography followed by MI surgery. Then 24 hours following MI, mice were randomized to either injection with 2x106 itMSCs (n=16) or saline control (n=16). Echocardiography was repeated at days 3, 7 and 21. Blood, spleen and hearts were then harvested; study researchers performed TTC staining of the hearts — below the level of coronary ligation — and flow cytometry of the spleen. Data are presented as Mean ± SEM.
- Results: Radiolabeled itMSCs preferentially trafficked to regions of myocardial injury, although the total number of the injected cells that engrafted in the myocardium was small. There was minimal trafficking to control mice without MI. Results found no difference in percent LV infarction by TTC staining (28±3% for itMSC group vs. 25±3% for control group). Control saline-treated mice with large infarcts (≥25% LV) demonstrated an increase in adverse LV remodeling vs. mice with small infarcts: end systolic volume in large vs. small infarcts was 77±20 uL vs. 33±3 uL (p=0.04) and end diastolic volume was 112±17 uL vs. 68±5 uL (p=0.03). With itMSC treatment, however, mice with large infarcts did not demonstrate an increase in adverse remodeling vs. mice with small infarcts: end systolic volume in large vs. small infarcts was 41±8 vs. 35±4 uL (p=0.53) and end diastolic volume was 79±8 uL vs. 70±6 uL (p=0.47), thus demonstrating that itMSCs prevented the adverse LV remodeling occurring in mice with large infarcts. In addition, both systolic and diastolic posterior wall thickness were greater in the itMSC group, and anterior wall thickening was greater during systole (p=0.01) compared with the control group. Importantly, itMSC injection resulted in a significant decrease in splenic NK cells compared with control injection (2.6±0.13 vs. 3.4±0.36, p<0.04). In vitro transwell experiments demonstrated itMSCs significantly suppress NK cell proliferation through paracrine effects.
- Authors: Michael J. Lipinski, Dror Luger, Peter C. Westman, David K. Glover, Julien Dimastromatteo, Juan Carlos Frias, M. Teresa Albelda, Sergey Sikora, Ron Waksman and Stephen E. Epstein
Stem cells are commonly thought to improve cardiac outcomes by myocardial regeneration or other direct effects from stem cells engrafting themselves in the myocardium. Thus, the concept is that the greater the number of myocardial engrafted stem cells, the better. Since IV itMSC delivery results in very low numbers of cells engrafting in damaged myocardium, catheter- or surgical-based stem cell delivery has been – with rare exception – the sole delivery strategy tested in clinical trials.
The hypotheses explored in this study are predicated on very different paradigms. Compelling evidence suggests that adult stem cells do not lead to myocardial regeneration and that excessive immune or inflammatory responses are one of the key mechanisms that cause progressive myocardial deterioration in AMI patients. This study tested the validity of two hypotheses:
- Intravenously administered itMSCs grown under chronic hypoxic conditions improve myocardial function and adverse remodeling in a murine AMI model.
- If functional benefit occurs, itMSC-induced systemic anti-inflammatory effects play an important mechanistic role.
Both hypotheses were proven to be valid.
Only CardioCell's therapies feature itMSCs, which are exclusively licensed from CardioCell's parent company Stemedica. Unlike MSCs grown under normoxic conditions, Stemedica's bone-marrow-derived, allogeneic itMSCs are grown under hypoxic conditions. In vivo experiments demonstrate cells that are exposed to hypoxic conditions show greater homing and engraftment than cells grown under normoxic conditions. Compared to MSCs manufactured under normal oxygen condition, itMSCs secrete higher levels of growth factors and other important proteins associated with neoangiogenesis and healing.
About CardioCell LLC
Founded in San Diego, California, in 2013, CardioCell LLC is a global biotechnology company that explores therapeutic applications of unique, patented, ischemia-tolerant mesenchymal stem cells manufactured under cGMP conditions. CardioCell is a subsidiary of Stemedica Cell Technologies Inc., a global biotechnology company that manufactures adult allogeneic stem cells. The company's technology is based on more than 30 years of research and clinical experience conducted by scientists and physicians in the United States, Europe and the former Soviet Union. CardioCell therapies offer a unique, proprietary technology based on the expansion of cells in constant hypoxia. The company has an exclusive, worldwide license from Stemedica to explore therapeutic indications for unmet cardiovascular needs, such as acute myocardial infarction, chronic heart failure and peripheral artery disease. For more information, visit www.stemcardiocell.com.
About Stemedica Cell Technologies Inc.
Stemedica Cell Technologies Inc. is a global biopharmaceutical company that manufactures best-in-class allogeneic adult stem cells and stem cell factors. The company is a government licensed manufacturer of cGMP, clinical-grade stem cells currently used in US-based clinical trials for acute myocardial infarction, chronic heart failure, cutaneous photoaging, ischemic stroke, Alzheimer's disease and traumatic brain injury. Stemedica's products are also used on a worldwide basis by research institutions and hospitals for pre-clinical and clinical (human) trials. Stemedica is currently developing additional clinical trials for other medical indications using adult, allogeneic stems cell under the auspices of the FDA and other international regulatory institutions. The company is headquartered in San Diego, California, and can be found online at www.stemedica.com.
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