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.

Donor Fat-Based Stem Cells May Provide Augmented Healing of Rectovaginal Fistulas of Crohn’s Disease Patients

Fistulas are openings in organ systems that connect with another system. They usually result from wounds or erosions in the lining of a tube or duct that gets deeper and deeper and eventually opens into another tube or duct. Physical injuries can cause fistulas, but so can diseases such as Crohn’s disease. Anal fistulas result from erosions of the rectum that open to the outside and are typically very painful and do not readily heal.

Damián García-Olmo and his colleagues at the Universidad Autónoma de Madrid have conducted several clinical trials that have examined the ability of adipose-derived stem cells (ASCs) to facilitate the healing of fistulas in Crohn’s disease patients. A phase I study, which primarily examines safety, was published in 2005 (see García-Olmo D., et al., Dis Colon Rectum 2005; 48:1416-1423). According to this study, “No adverse effects were observed in any patient at the end of the follow-up period (minimum follow-up, 12 months; maximum follow-up, 30 months; follow-up average, 22 months).” The Phase II study was published in 2009 (García-Olmo, D., et al., Dis Colon Rectum 2009; 52:79-86). According to the results of this study, fistula healing was observed in 71 percent of patients who were treated with ASCs in combination with fibrin glue compared with 16 percent of patients who received fibrin glue alone. Quality of life scores were also higher in patients who received ASCs than in those who received fibrin glue alone. Once again, the stem cell treatments were well tolerated. The third study was a multicenter, randomized, single-blind clinical trial that enrolled 200 adult patients from 19 centers that were randomly assigned to three groups. The first group received 20 million stem cells (group A, 64 patients). The second group received 20 million adipose-derived stem cells plus fibrin glue (group B, 60 patients). The third group received only fibrin glue (group C, 59 patients). In treatment of anal fistulas in Crohn’s disease patients, a dose of 20 or 60 million adipose-derived stem cells alone or in combination with fibrin glue were demonstrably safe and did promote healing. However, there were no statistically significant differences between the three groups once the 3 groups were compared.

These studies suggest that stem cells from fat might have a place in the treatment of fistulas in Crohn’s disease patients. The application of the stem cells is feasible and safe, and requires no new equipment or skill. The stem cells also might augment the healing of these fistulas.

Unfortunately, anal fistulas are not the only type of fistulas that Crohn’s disease patients can experience. Female Crohn’s disease patients can have fistulas that open from their rectum into their birth canal. These rectovaginal fistula can deposit the contents of the gastrointestinal tract into the lower reproductive tract. While Crohn’s disease is not the only cause rectovaginal fistulas, Crohn’s disease patients are at higher risks for complications, which include: loss of control over stool deposition (fecal incontinence), hygiene problems combined with recurrent vaginal or urinary tract infections, inflammation of the birth canal and skin around the anus (perineum), abscess formation, which can become life-threatening if not treated, and recurrence of the fistula. Surgical treatment of rectovaginal fistulas requires that the tissue be free of inflammation before surgery, which can take time and cause extensive amounts of patient suffering.

Garcia-Olmo and his colleagues have conducted a small phase I-IIa clinical trial to evaluate the possibility of banked fat-based stem cells to treat recto-vaginal fistulas in female Crohn’s patients. This study has several limitations because it is so small and they have to exclude at least half of the participants because of complications beyond their control. Therefore, this study is not statistically significant. However, it does show what might be the beginnings of a stem-based treatment for this horrid condition.

The design of the study included 11 subjects who were initially enrolled in the study, but one of those recruited patients did not meet the criteria for the study. Therefore, ten subjects, all of whom suffered from Crohn’s disease and had rectovaginal fistulas were treated with 20 million fat-based stem cells that had been donated by a healthy volunteer in addition to surgical repair of their fistulas. These donated fat-based stem cells were provided by a Spanish biotechnology company called Cellerix S.L. Three months after this stem cell treatment, two patients were healed and the other either were given an additional treatment of 40 million fat-based stem cells. Of this group, four were healed. However, five of these patients experienced severe flare-ups of their Crohn’s disease that required treatment with biological agents, which disqualified these patients from further consideration from this study. The biological agents used to treat the Crohn’s disease flare-ups are very powerful medicines and can significantly influence the outcome of this study. Thus half of the subjects in this study had to be excluded. Of the five subjects that remained, 3 showed healing of their fistulas, and 2 did not.

The authors present the data as a “final efficacy rate of 60%.” However, given the high rate of exclusion and the very low numbers of subjects in this study, all we can say with any confidence is that based on the previous successes of this treatment in other studies, there is precedent for such a technique to be safe and somewhat effective, and that the data in this study are in a favorable direction. However, that’s about it.

One feature of this study that differs from the other clinical trials done by this same group is that the previous studies utilized the patient’s own fat-based stem cells, whereas this study used stem cells from a healthy donor. The authors stress that this modification greatly simplifies the procedure and decreases its expense. Because of the ease of the treatments, it reduces postoperative hospitalization and is minimally invasive. This new trial suggests that further work is warranted and the results or even minimally hopeful.

This work was published in the journal Stem Cells Translational Medicine 2016; 5(11): 1441-1446.