Intravenous Preconditioned Mesenchymal Stem Cells from Donors Improve the Heart Function of Heart Failure Patients


CardioCell is a global biotechnology company that was founded in 2013 in San Diego, California. CardioCell specializes in ischemia-tolerant mesenchymal stem cells (itMSCs). These stem cells are derived from bone marrow-derived mesenchymal stems extracted from healthy donors. However, after isolation, these cells are grown in low-oxygen conditions, which induces the expression of genes that allow cells to adapt to stressful, oxygen-poor conditions.

Non-ischemic dilated cardiomyopathy (NIDCM) is a progressive disorder with no current cure, often culminating in heart transplantation. Because the heart has enlarged, there are areas where the blood supply of the heart fails to properly provide oxygen to the tissues. Without proper muscular support, the walls of the heart begin to thin and the blood supply becomes less and less adequate to the task of feeding the heart muscle. Also, the heart of a patient experiencing chronic heart failure also seems to have some low-level of inflammation that slowly damage the heart (Circ Res. 2016;119(1):159-76). Stem cell treatments might help ameliorate the physiological quandary in which the heart finds itself, but these oxygen-poor areas of the heart are inimical to stem cell survival and flourishing. Therefore, itMSCs stand a better chance of surviving when implanted into a damaged heart than non-conditioned stem cells. Experiments in laboratory animals have confirmed that itMSCs show a greater ability to seek out and find the damaged heart and engraft into the heart at higher rates than MSCs grown under normal culture conditions (see PLoS One. 2015 Sep 18;10(9):e0138477; Stem Cells. 2015 Jun;33(6):1818-28). These itMSCs also secrete higher levels of growth factors and angiogenic factors than normal MSCs. On the strength of these laboratory and animal-based studies itMSCs are now in the process of being tested as a treatment for heart attack patients.

CardioCell has sponsored a single-blind, placebo-controlled, crossover, randomized phase II-a trial of patients with NIDCM who have an ejection below 40% (the ejection fraction refers to the average percentage of blood pumped from the left ventricle at each contraction. The average ejection from for a healthy individual is about 65% or so).  The results of this study were published in the journal Circulation Research (;

Patients who volunteered for this study were randomly assigned to group I or group II. Group I patients received intravenous infusions of one and a half-million itMSCs per kilogram body weight. Group II received the placebo. There were 22 patients in all, and 10 received the itMSCs and 10 received the placebo. Since this was a crossover trial, after 90 days, patients in group I received he placebo and group II received the intravenous itMSCs. After crossover, safety and efficacy data were available for all 22 itMSC patients.

With respect to safety issues, there were no major differences in the number of deaths, hospitalizations, or serious adverse events between the two treatments. With respect the efficacy, the data is but more difficult to analyze. In the first place, when it comes to changes in the ejection fraction of the left ventricle from the originally measured baseline, there were no statistically significant changes between the two treatments. The same could be said for the volume of the left ventricle. This is an unfortunately finding, since heart failure includes a decrease in the ejection fraction of the heart and stretching and dilation of the ventricles. Stem cell treatments, if they are to properly treat heart failure, should increase the ejection fraction of the heart and reduce the dilation of the left ventricle. However, there might be more to these data than originally meets the eye. When it came to patient performance, the data was much more hopeful. Compared to patients who received the placebo, patients who received the itMSCs significantly increased the distance they were able to walk during 6-minutes. Patients who had received the itMSCs walked an average of 36.47 longer meters than patients who had received the placebo. Additionally, patients were also given a commonly-used survey, called the Kansas City Cardiomyopathy clinical summary. This survey is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. Administration of this survey to both sets of patients revealed that patients who had received the itMSCs consistently and statistically significantly scored higher on this survey than those patients who received the placebo. The same was also demonstrated for particular functional status tests. Therefore, when it came to how well patients felt and well they functioned, itMSC treatments seemed to excel significantly better than placebo.

Given the ability of MSCs to suppress inflammation, and given the tendency for patients with heart failure to suffer from chronic inflammation of the heart, individual patients were measured for their degree of inflammation. There was an inverse relationship between the degree of inflammation in a patient and their ejection fraction; the lower their level of inflammation, the higher their ejection fraction.

Thus this study seems to suggest that treatment of heart failure with itMSCs is indeed safe. These treatments also did reduce inflammation in heart failure patients and these reductions in inflammation were also associated with improvements in health status and functional capacity.

CardioCell LLC Clincal Trial Tests Ischemia-Resistant Mesenchymal Stem Cells in Heart Failure


The cell therapy company CardioCell LLC has completed enrolling 23 patients for its Phase 2a chronic heart failure trial. These subjects were enrolled at Emory University in Atlanta, GA, MedStar Washington Hospital Center in Washington DC, and three other hospitals.

This study has the ponderous title of “Single-blind, Placebo-controlled, Crossover, Multicenter, Randomized Study to Assess the Safety, Tolerability and Preliminary Efficacy of Single Intravenous Dose of Ischemia-tolerant of Allogeneic Mesenchymal Bone Marrow Cells to Subjects With Heart Failure of Non-ischemic Etiology.”

This clinical trial will examine the safety of CardioCell’s proprietary ischemic-tolerant mesenchymal stem cells in heart failure patients. The trial will also test the ability of these cells to improve the heart function of these safe patients.

Ischemia-resistant mesenchymal stem cells have are extracted from bone marrow and then subjected to harsh cell culture conditions that toughen them up and improves their therapeutic capacities.

Cardiologist Javed Butler said that this clinical trial has been designed to use this novel intervention in a carefully selected group of patients who met rigorous inclusion and exclusion criteria.

This trial will deliver ischemia-tolerant mesenchymal stem cells (itMSCs) by means of intravenous infusion into heart failure patients and then monitor these patients to determine if the itMSC-treated patients show signs of improvement in heat function.

These itMSCs are licensed under the parent company Stemedica and these are allogeneic cells that were isolated from young, healthy donors and grown under hypoxic conditions. Once grown under these harsh culture conditions, the itMSCs increase their ability to home to damaged tissues and engraft into those tissues. itMSCs also secrete increased levels of growth and trophic factors that promote neurogenesis and tissue healing.

Novastem Treats Its First Stroke Patient With Stemedica’s Mesenchymal and Neural Stem Cell Combination


The biotech company Novastem is a leader in regenerative medicine and has announced the treatment of its first patient in its clinical study for ischemic stroke at Clinica Santa Clarita, Mexico. This clinical trial is testing cell products made by Stemedica. In particular, Stemedica’s ischemia-tolerant mesenchymal stem cells (itMSCs) were administered in combination with ischemia-tolerant neural stem cells (itNSCs); both of which are proprietary products of Stemedica.

Stemedica‘s itMSCs and itNSCs are unique because of the manner in which they are manufactured – they are grown under conditions that make them resistant to low-oxygen conditions. Experiments conducted with these cells in culture and in living animals have definitely shown that when these cells are exposed to low-oxygen conditions, they show greater homing and engraftment than cells grown under normal conditions. Compared to other MSCs and NSCs, Stemedica’s stem cells secrete higher levels of growth factors and other important proteins associated with angiogenesis and healing.

According to the American Stroke Association, ischemic strokes account for 87 percent of all stroke cases. Novastem is continuing to enroll qualified patients in their study. This clinical trial is entitled “Internal Research Protocol in Combination Therapy of Intravenous Administration of Allogeneic Mesenchymal Stem Cells and Intrathecal Administration of Neural Stem Cells in Patients with Motor Aphasia due to Ischemic Stroke.” All participants in this clinical trial will receive a unique, combination stem cell therapy consisting of cells made by Stemedica Cell Technologies.

Novastem is sponsoring this clinical trial and Novastem is the only company licensed to use Stemedica’s stem cell products for studies in Mexico. Novastem’s Clinica Santa Clarita facility is federally licensed to use stem cell therapies, and this trial marks the first time ischemic stroke is being treated with a patented medical method that comprises administration of hypoxically-grown neural stem cells into the cerebrospinal fluid in combination with intravenous administration of hypoxically-grown mesenchymal stem cells. This combination approach is designed to treat the after effects of ischemic strokes.

“Novastem and Clinica Santa Clarita are committed to advancing the research of neurodegenerative disease, and we are pleased to be working with internationally-recognized physician Clemente Humberto Zuniga Gil, MD as the principal investigator and study designer,” says Rafael Carrillo, Novastem’s President. “Our medical team believes that Stemedica’s mesenchymal and neural stem cells, used in this unique combination therapy, will restore and build new vascularization, improve the blood supply, reconnect damaged neural networks and improve functionality of areas affected by our patients’ ischemic stroke.”

The aim of this Novastem study is to evaluate functional changes on subjects after the administration of ischemia-tolerant mesenchymal and neural stem cells. The protocol in use in this clinical trial has been approved by the Research Ethics Committee of Clinica Santa Clarita, which is federally registered and licensed by the Federal Commission for the Protection against Sanitary Risk (COFEPRIS), a division of Mexico’s Ministry of Health.

Patient progress will be tracked at the beginning of the study before any cells have been administered, at 90 days after stem cell administration, and then again at 180 days after administration. Patient improvement will be ascertained with the United States National Institute of Health Stroke Score (NIHSS), Stroke and Aphasia Quality of Life Scale-39 (SAQCOL-39) and the Boston Diagnostic Aphasia Examination (BDAE) neuropsychological evaluation for diagnosis. Additionally, MRIs taken with a gadolinium-based contrast agent (GBCA) will examine the structural integrity of the brain before and after stem cell administration. At the endpoint, the treatment will be evaluated for safety and tolerance of the two-cell treatment. Additionally, patients will be evaluated for changes in neurological functionality.

New US Phase IIa Trial and Phase III Trial in Kazakhstan Examine CardioCell’s itMSC Therapy to Treat Heart Attack Patients


The regenerative medicine company CardioCell LLC has announced two new clinical trials in two different countries that utilize its allogeneic stem-cell therapy to treat subjects with acute myocardial infarction (AMI), which is a problem that faces more than 1.26 million Americans annually. The United States-based trial is a Phase IIa AMI clinical trial that is designed to evaluate the clinical safety and efficacy of the CardioCell Ischemia-Tolerant Mesenchymal Stem Cells or itMSCs. The second clinical trial in collaboration with the Ministry of Health in Kazakhstan is a Phase III AMI clinical trial on the intravenous administration of CardioCell’s itMSCs. This clinical trial is proceeding on the strength of the efficacy and safety of itMSCs showed in previous Phase II clinical trials.

CardioCell’s itMSCs are exclusively licensed from CardioCell’s parent company Stemedica Cell Technologies Inc. Normally, when mesenchymal stem cells from fat, bone marrow, or some other tissue source are grown in the laboratory, the cells are provided with normal concentrations of oxygen. However, CardioCell itMSCs are grown under low oxygen or hypoxic conditions. Such growth conditions more closely mimic the environment in which these stem cells normally live in the body. By growing these MSCs under these low-oxygen conditions, the cells become tolerant to low-oxygen conditions (ischemia-tolerant), and if transplanted into other low-oxygen environments, they will flourish rather than die.

Another advantage of itMSCs for regenerative treatments over other types of MSCs is that itMSCs secrete higher levels of growth factors that induce the formation of new blood vessels and promote tissue healing. These clinical trials have been designed to help determine if CardioCell’s itMSC-based therapies stimulate a regenerative response in acute heart attack patients.

“CardioCell’s new Phase IIa AMI study is built on the excellent safety data reported in previous Phase I clinical trials using our unique, hypoxically grown stem cells,” says Dr. Sergey Sikora, Ph.D., CardioCell’s president and CEO. “We are also pleased to report that the Ministry of Health in Kazakhstan is proceeding with a Phase III CardioCell-therapy study following its Phase II study that was highly promising in terms of efficacy and safety. Our studies target AMI patients who have depressed left ventricular ejection fraction (LVEF), which makes them prone to developing extensive scarring and therefore to the development of chronic heart failure. CardioCell hopes our itMSC therapies will inhibit the development of extensive scarring and, thus, the occurrence of chronic heart failure in these patients.”

The United States-based Phase IIa clinical trial will take place at Emory University, Sanford Health and Mercy Gilbert Medical Center. The CardioCell Phase IIa AMI trial is a double-blinded, multicenter, randomized study designed to assess the safety, tolerability and preliminary clinical efficacy of a single, intravenous dose of allogeneic mesenchymal bone-marrow cells infused into subjects with ST segment-elevation myocardial infarction (STEMI).

“While stem-cell therapy for cardiovascular disease is nothing new, CardioCell is bringing to the field a new, unique type of stem-cell technology that has the possibility of being more effective than other AMI treatments,” says MedStar Heart Institute’s Director of Translational and Vascular Biology Research and CardioCell’s Scientific Advisory Board Chair Dr. Stephen Epstein. “Evidence exists demonstrating that MSCs grown under hypoxic conditions express higher levels of molecules associated with angiogenesis and healing processes. There is also evidence indicating they migrate with greater avidity to various cytokines and growth factors and, most importantly, home more robustly to ischemic tissue. Studies like those underway using CardioCell’s technology are designed to determine if we can evoke a more potent healing response that will reduce the extent of myocardial cell death occurring during AMI and thereby decrease the amount of scar tissue resulting from the infarct. A therapy that could achieve this would have a major beneficial impact in reducing the occurrence of chronic heart failure.”

Kazakhstan’s National Scientific Medical Center is conducting a Phase III AMI clinical trial using CardioCell’s itMSCs, which are sponsored by local licensee Altaco. This clinical trial is entitled, “Intravenous Administration of itMSCs for AMI Patients,” and is proceeding based on a completed Phase II efficacy and safety study. However, the results of this previous Phase II study are preliminary because the sample group was so small. Despite these limitations, the findings demonstrated statistically significant elevation (more than 12 percent over the control group) in the ejection fraction of the left ventricle of the heart in patients who had received itMSCs. Also, a significant reduction in inflammation was also observed, as ascertained by lower CRP (C-reactive protein) levels in the blood of treated patients in comparison to control groups. Thus, Dr. Daniyar Jumaniyazov, M.D., Ph.D., principal investigator in Kazakhstan clinical trials states: “In our clinical Phase II trial for patients with AMI, treatment using itMSCs improved global and local myocardial function and normalized systolic and diastolic left ventricular filling, as compared to the control group. We are encouraged by these results and look forward to confirming them in a Phase III study.”

CardioCell’s treatment is the first to apply itMSC therapies for cardiovascular indications like AMI, chronic heart failure and peripheral artery disease. Manufactured by CardioCell’s parent company Stemedica and approved for use in clinical trials, itMSCs are manufactured under Stemedica’s patented, continuous-low-oxygen conditions and proprietary media, which provide itMSCs’ unique benefits: increased potency, safety and scalability. itMSCs differ from competing MSCs in two key areas. itMSCs demonstrate increased migratory ability towards the place of injury, and they show increased secretion of growth and transcription factors (e.g., VEGF, FGF and HIF-1), as demonstrated in a peer-reviewed publication (Vertelov et al., 2013). This can potentially lead to improved regenerative abilities of itMSCs. In addition, itMSCs have significantly fewer HLA-DR receptors on the cell surface than normal MSCs, which might reduce the propensity to cause immune responses. As another benefit, itMSCs are highly scalable. A single donor specimen can currently yield about 1 million patient treatments, and this number is expected to grow to 10 million once full robotization of Stemedica’s facility is complete.