Temple University Lab Shows Exosomes from Stem Cells Heal Hearts After a Heart Attack


Temple University stem cell researcher Raj Kishore, who serves as the Director of the Stem Cell Therapy Program at the Center for Translational Medicine at Temple University School of Medicine (TUSM), and his colleagues have used exosomes from stem cells to induce tissue repair in the damaged heart. The results of this fascinating research made the cover of the June 19, 2015 edition of the leading cardiovascular research journal, Circulation Research.

“If your goal is to protect the heart, this is a pretty important finding,” Dr. Kishore said. “You can robustly the heart’s ability to repair itself without using the stem cells themselves. Our work shows a unique way to regenerate the heart using secreted vesicles from embryonic stem cells.” Kishore’s group is in the early stages of characterizing the molecules in these exosomes that are responsible for inducing and potentiating tissue repair.

The heart beats throughout the lifetime of an individual. Despite its apparent constancy, the heart possess little to no ability to repair itself. When heart muscle is damaged in a heart attack, the heart is unable to replace the dead tissue and grow new contracting heart muscle. Instead, after a heart attack, it compensates for lost pumping ability by enlarging, a phenomenon known as ”remodeling.” .Remodeling, however, come with a high price, since the heart grows beyond the ability of the sparse cardiac circulatory system to properly convey blood to the enlarged heart muscle. Consequently, heart contraction weakens, leading to a condition known as congestive heart failure, which contributes to, or causes one in nine deaths in the United States. Heart disease is our nation’s leading killer.

Given the fact that heart disease is the result of the death of heart muscle cells, this condition seems to tailor-made for stem cell therapy. A variety of animal experiments with stem cells from bone marrow, muscle, fat, or embryos have shown that stem cells can regenerate heart muscle. However, the regeneration of the heart is much more complicated than was originally thought. For example, injecting damaged hearts with stem cells turned out to be a rather ineffective strategy because the heart, after a heart attack, is a very hostile place for newly infused cells. Dr. Kishore noted, “People know if they inject hundreds of stem cells into an organ, you’re going to be very lucky to find two of them the next day. They die. It’s as though you’re putting them into the fire and the fire burns them.”

Dr. Kishore has used a very different approach for regenerative medicine. Over 10 years ago, cancer researchers discovered tiny sacks excreted by cells that they called “exosomes.” These exosomes were thought to be involved with waste disposal, but later work showed that they were more mini-messengers, carry telegrams between cells. Exosomes proved to be one way a primary tumor communicated with distant metastases. Researchers later discovered that nearly all cell types excrete exosomes. Dr. Kishore and his team began to study the exosomes of stem cells to determine if these small vesicles could solve the heart-repair problem.

In 2011, Kishore’s team published the first paper to ever examine stem cell exosomes and heart repair. This paper established Kishore and his research team as a pioneer in exosome research and in the use of exosomes in the treatment of heart disease. A year after that paper, there were a total of 52 papers published on exosomes, but today there are 7,519 papers reporting on exosome research. Among those studies, only 13 or 14 have examined exosomes in heart disease. This new paper by Dr. Kishore’s team marks its third contribution to the science of exosomes and heart repair.

In the current study, Kishore and others used a mouse model of heart attack. Also involved in the research are Dr. Kishore’s colleagues from Temple’s Center for Translational Medicine, the Cardiovascular Research Center, and the Department of Pharmacology, as well as researchers from the Feinberg Cardiovascular Research Institute at Northwestern University in Chicago.

In this study, after suffering a heart attack, the mice received exosomes from either embryonic stem cells or exosomes from fibroblasts. Mice that received the fibroblast-derived exosomes served as the control group. The results were unmistakable. Mice that received exosomes from embryonic stem cells showed significantly improved heart function after a heart attack compared to the control group. More heart muscle cells in these mice survived after the heart attack, and their hearts also exhibited less scar tissue. Fewer heart cells committed suicide — a process known as programmed cell death, or apoptosis. Also, hearts from mice treated with embryonic stem cell-derived exosomes showed greater capillary development around the areas of injury. The increased density of blood vessels improved circulation and oxygen supply to the heart muscle. Further, there was a marked increase in endogenous cardiac progenitor cells, which is the hearts own internal stem cell population. These cells survived and created new heart cells. The heartbeat was more powerful in the experimental group compared to the control group, and the kind of unhealthy enlargement that compensates for tissue damage was minimized.

Vishore’s group also tested the effect of one of the most abundant gene-regulating molecules (microRNAs) found in the stem cell exosome; a microRNA called miR-294. When purified miR-294 alone was introduced to cardiac stem cells in the laboratory, it mimicked many of the effects seen when the entire exosome was delivered. “To a large extent, this micro-RNA alone can recapitulate the activity of the exosome,” Dr. Kishore said. “But we can never say it is responsible for all of the response because embryonic stem cell exosomes have many other microRNAs.”

Future research will examine both exosome therapy and the use of specific microRNAs for heart repair in large-animal models of heart attack with a view to eventually testing these components in human patients in clinical trials.

“Our work shows that the best way to regenerate the heart is to augment the self-repair capabilities and increase the heart’s own capacity to heal,” Dr. Kishore said. “This way, we’re avoiding risks associated with teratoma formation and other potential complications of using full stem cells. It’s an exciting development in the field of heart disease.”

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How Cardiospheres Heal the Heart


In 2007, Eduardo Marbán and his colleagues have discovered a stem cell population from the hearts of mice and humans that grow as small balls of cells in culture (see RR Smith, et al., Circulation. 2007 Feb 20;115(7):896-908). He called these cells “cardiospheres” and in a follow-up study showed that these cells have the ability to differentiate into heart muscle cells, blood vessel cells, or other types of heart-specific cells (PV Johnson, et al., Circulation. 2009 Sep 22;120(12):1075-83). Other animal experiments by Marban’s group showed that not only were cardiospheres easily obtained by means of heart biopsies, but injection of these cells directly into the heart after a heart attack augmented healing of the heart and accelerated the recovery of heart function and while preserving heart structure (ST Lee, et al., J Am Coll Cardiol. 2011 Jan 25;57(4):455-65; CA Carr, et al., PLoS One. 2011;6(10):e25669; Shen D, Cheng K, Marbán E. J Cell Mol Med. 2012 Sep;16(9):2112-6).

All of these very hopeful results in culture and in animal studies eventually gave way to a small human clinical trial in which a heart patient’s own cardiospheres were transplanted into their own hearts.  This clinical trial, the CADUCEUS trial (which stands for cardiosphere-derived autologous stem cells to reverse ventricular dysfunction), prevent patient’s hearts from worsening, but more remarkably, the heart scars of these patients were partially erased 6 months after treatment.  A one-year follow-up showed that patients had improved global heart function that directly correlated to the shrinkage of their heart scars.

These results are very encouraging and Marbán made it clear that he wants to conduct larger clinical trials.  However, he still had a gaggle of unanswered questions about his cardiospheres.  Do these cells affect blood vessel formation?  Can they prevent the enlargement of the heart that occurs after a heart attack (known as cardiac remodeling)?  Can the benefits of these cells be solely linked to their effects on the heart scar?  Do cardiospheres prevent the formation of the heart scar?  Do they only help heal the area of the heart where they are administered or do they also help more far-flung regions of the heart?  These are all good questions, and answers to them are necessary if Marbán and his group is to conduct larger and more intense clinical trials with human heart patients.  Therefore, he turned to an animal model system to address these questions in detail.  In particular, he chose Wistar Kyoto rats.

Readers of this blog will recognize the experimental strategy; break the rats into three groups, induce experimental heart attacks in two groups, give one group cultured cardiospheres and leave the other one alone.  Thus you have a sham group that underwent surgery but was not given a heart attack, a heart attack group that did not receive cardiospheres, and a heart attack group into which 2 million rat cardiospheres were injected at four different sites near the site of the infarct.

This experiment, did far more than simply monitor the heart function of the animals for several weeks.  Instead, some of these animals were sacrificed and their hearts were subjected to extensive biochemical and molecular biological tests.   The goal of these experiments was to determine not just if the cardiospheres helped heal the heart.  Marbán and his group already knew that they do.  They wanted to know how they heal the heart.

The cardiosphere-treated animals showed substantial improvements in their heart function as opposed to their non-treated counterparts.  The treated animals had heart that did not undergo remodeling and also pumped better.  Hearts from the cardiosphere-treated animals had less dead heart tissue and more live tissue.  They had smaller heart scars, and better preservation of cellular structure in the heart.  When biochemical markers of proliferating cells were measured in these hearts, the cardiosphere-treated hearts showed robust increases in cell proliferation far above those hearts that were not treated with cardiospheres.  Thus cardiospheres seem to induce resident heart cells to divide and replace dead and dying heart cells.

A common response to a heart attack is that the surviving heart cells enlarge (hypertrophy).  The cardiosphere-treated hearts showed no such response.  Also, when the blood vessel density of the heart tissue was determined, the cardiosphere-treated hearts had close the twice the vessel density of the non-treated hearts.  This was the case near the site of cardiosphere injection, but it also held, albeit not as robustly, in areas far from the site of cardiosphere injection.  This suggests that blood vessel formation is due to secreted molecules.

To test this possibility, Marbán and his crew rigged a culture assay in which rings of tissue from the aorta (the largest blood vessel in the body), were embedded in collagen and treated with culture media from cardiospheres, standard culture cell culture media, or cell culture medium from endothelial cells.  The cardiosphere culture medium, which contains a cocktail of molecules secreted by growing cardiospheres as they have grown in culture, induced far more blood vessels in this system than the other two.  This confirms the notion that cardiospheres secrete blood vessels-inducing molecules that this increases the vascularization of the heart muscle, this aiding its survival.

Marbán and his team also examined the molecule that forms the heart scar; collagen and how cardiospheres affect the synthesis and deposition of collagen.  They discovered that cardiospheres actually degrade the collagen at the heart scar.  They showed that cardiosphere secrete enzymes that have been documented to degrade collagen (Matrix Metalloproteases 2 and 13 for those who are interested).  Marbán and others also discovered that cardiospheres put the kibosh on collagen synthesis.  When they measured biochemical markers of collagen synthesis (hydroxyproline), they were present at rather low levels.  Thus cardiospheres prevent the deposition of the heart scar and also actively degrade it.

Thus, Marbán and his colleagues showed that cardiospheres: 1) prevent the tissue-level changes associated with cardiac remodeling; 2) preserve heart function locally and globally; 3) increase the proliferation of heart muscle cells at the site of the infarct, and to a lesser effect, throughout the heart; 4) induce the formation of new blood vessels at the site of injection, and, to a lesser extend, further from the site of cardiosphere injection; and 5) actively prevent the formation of the heart scar by inhibiting its formation and degrading whatever collagen has been deposited.

Thus cardiospheres decrease the formation of collagen and therefore, decrease the stiffness of the wall of the heart.  They also product new blood vessels and provide a supportive environment for the formation of new heart muscle cells.

This paper was published in PLoS One (2014) 9(2):e88590.

May Marbán’s clinical trials increase!!

Preserving Heart Tissue After a Heart Attack: Umbilical Cord-Coated Stem Cell Spheres


Eliana Martinez and her colleagues from the laboratories of Chuen Lee and Theo Kofidis at the National University of Singapore have published an extremely interesting paper in the journal Stem Cells and Development. In this paper, Martinez and her colleagues use a novel approach to deliver stem cells to the hearts of rats after a heart attack.

Usually, stem cells are given to heart attack patients in one of several ways. In laboratory animals, it is common to simply inject the stem cells directly into the heart muscle. This is done after the animals’ chest has been cut open. This procedure, known as a thoracotomy, is feasible in human patients, but unless the patient is undergoing coronary artery graft bypass surgery, cracking the chest leaves the patients in severe pain, greatly weakened, and with a very long recovery period. Therefore, unless necessary, this procedure is not preferred. Secondly, stem cells are delivered through the coronary arteries by means of the same technology used to deliver stents (percutaneous coronary intervention or PCI). In this case the cells are delivered through the coronary arteries while the arteries are propped open. This procedure is relatively easy to perform and no special equipment or training is required to deliver the cells, but several studies have shown that only a fraction of the cells make it to the heart muscle. The third technique uses direct injection into the heart muscle without cracking the patient’s chest. This technique uses special injection devices under the direction of sophisticated heart imaging technologies. Special equipment and specialized training is required to deliver the cells. Only a few centers offer this mode of delivery. The cells are well retained in the heart muscle, but a percentage of them leak out and find their way into the lung and other organs.

All of these techniques have their ups and downs. To that end, Martinez and her colleagues decided to deliver small spheres of stem cells surrounded by umbilical cord cells. These subamnion-cord-lining mesenchymal stem cell angiogenic spheroids (say that fast five times) consist of a special cell type from human umbilical cord called human umbilical cord vein endothelial cells or HUVECs that were used to encase another type of umbilical cord stem cell called cord-lining mesenchymal stem cells or CL-MSCs.

CL-MSCs have been evaluated in the laboratory and they seem to possess a robust ability to evade detection by the immune system and suppress inflammation, and do a better job of inducing healing than bone marrow-based stem cells (see Deuse T, et al., Cell Transplant. 2011;20(5):655-67). These cells also showed a marked ability to repair the heart after a heart attack (see Lilyana and others, Tissue Eng Part A 19:1303-1315).

To this end, Kofidis and his co-workers decided to use the spheroid technique because stem cells grown in liquid suspension and not flat culture dishes seem to do a better job of holding onto their healing properties than stem cell grown under standard conditions. Next, Martinez and others added HUVEC cells, which make blood vessels, the encase the CL-MSCs. Once they spheroids were made, they used fibrin (the protein found in blood clots) to paste the spheroids to the heart tissue after inducing a heart attack in laboratory rats.

These spheroids were mercifully called SASGs, since the proper name of these clusters was subamnion-cord mesenchymal stem cells angiogenic spheroids embedded within fibrin grafts (exhale). The laboratory animals were either given fibrin grafts without SASGs, neither fibrin grafts nor SASGs, and SASGs while the animal had its chest cracked, SASGs delivered without a thoracotomy (under video-assisted thoracoscopic surgery, and fibrin grafts under with no SASGs without have the chest cracked open.

In both cases in which SASGs were delivered, the structure and function of the heart improved in every physiological category examined. The heart beat more efficiently, the heart scar was smaller, there were more blood vessels, less, cell death, less sign of heart failure,

Even though this was a relatively small study in laboratory animals, it shows that a minimally invasive procedure can deliver stem cells to the heart that will stay in the heart and deliver healing to it,

This strategy should be expanded to larger numbers of animals and then, if it still statistically pans out, larger animal model systems should be examined (e.g., minipigs).   This is an ingenious technique, and hopefully, other laboratories will confirm the efficacy of this technique and the robust healing capabilities of this particular stem cell type from umbilical cord.

Caduceus Clinical Trial One-Year Update


The CADUCEUS clinical trial, which stands for CArdiosphere-Derived aUtologous stem CElls, to reverse ventricUlar dySfunction) was the brainchild of Cedar-Sinai cardiologist Eduardo Marbán and his colleagues. 

This CADUCEUS trial used a heart-specific stem cell called CDCs or cardiosphere-derived cells to treat patients who had recently suffered a heart attack.  CDCs are extracted from the patient’s own heart and they can be grown in culture, expanded, and then implanted back into the patient’s heart. The initial assessments of those patients who had received the stem cell treatments was published in 2012 in the Journal Lancet (R.R. Makkar, R.R. Smith, K. Cheng et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet, 379 (2012), pp. 895–904). The initial assessments of these patients showed shrinkage of their heart scars.  However, these patients showed regional improvements in heart function but no significant differences in global heart function.  Despite these caveats, the initial results were hopeful. 

Now the one-year follow-up of these patients has been published in the Journal of the American College of Cardiology.  The results of this examination are even more exciting.

CDCs were extracted from patients by means of heart biopsies of the inner part of the heart muscle (myocardium). After the cells were grown in culture to larger numbers, they were reintroduced to the hearts of the patients by means of “stop-flow” technique. This procedure utilizes the same technology as stents in that an over-the-wire balloon angioplasty catheter that was positioned in the blood vessels on the heart that were blocked. The figure below shows the cultured cardiospheres.

Specimen processing for human cardiosphere growth and CDC expansion. a, Schematic depicts the steps involved in specimen processing. b, Endomyocardial biopsy fragment on day 1. c, Explant 3 days after plating. d, Edge of explant 13 days after plating showing stromal-like and phase-bright cells. e, Cardiosphere-forming cells collected from the explant after 13 days and plated on poly-d-lysine for 2 days. f, Fully formed cardiospheres on day 25, 12 days after collection of cardiosphere-forming cells. g, CDCs during passage 2, plated on fibronectin for expansion. h and i, Cell growth is expressed as number of population doublings from the time of the first harvest for specimens from nontransplant patients (h) and specimens from transplant patients (i).
Specimen processing for human cardiosphere growth and CDC expansion. a, Schematic depicts the steps involved in specimen processing. b, Endomyocardial biopsy fragment on day 1. c, Explant 3 days after plating. d, Edge of explant 13 days after plating showing stromal-like and phase-bright cells. e, Cardiosphere-forming cells collected from the explant after 13 days and plated on poly-d-lysine for 2 days. f, Fully formed cardiospheres on day 25, 12 days after collection of cardiosphere-forming cells. g, CDCs during passage 2, plated on fibronectin for expansion. h and i, Cell growth is expressed as number of population doublings from the time of the first harvest for specimens from nontransplant patients (h) and specimens from transplant patients (i).

The initial assessment of these patients showed shrinkage of the heart scar and regional improvements in heart function. However in the one-year follow-up the scar showed even more drastic shrinkage (-11.9 grams or -11.1% of the left ventricle). Also, several of the indicators of global heart function showed substantial improvements (end-diastolic volume – -12.7 mls and end-systolic volume – -13.2 mls).

When it come to the all-important ejection fraction, which is the percentage of blood pumped from the left ventricle, the results are a little more complicated. When the ejection factions of each patient was compared with the size of their heart scars, there was a tight correlation between the increase in ejection fraction and the shrinkage of the heart scar. See the figure below for a scatter plot of ejection fraction versus heart scar size.

(A) Scatterplot showing the natural relationship between scar size and left ventricular ejection fraction ∼5 months post-myocardial infarction (circles). Each cross symbol represents the mean values (at the intersection of the vertical and horizontal bars [obtained from all patients with magnetic resonance imaging measurements]), whereas the width of each bar equals ±SEM of scar size and left ventricular ejection fraction of CADUCEUS patients at baseline, 6 months, and 1 year; the crosses are superimposed onto the scatterplot showing prior data from post-myocardial infarction patients with variable scar sizes. The changes in left ventricular ejection fraction in CDC-treated subjects are consistent with the natural relationship between scar size and ejection fraction in convalescent myocardial infarction, whereas the changes in left ventricular ejection fraction in controls fall within the margins of variability. (B) Changes in end-diastolic volume from baseline to 1 year. (C) Changes in end-systolic volume from baseline to 1 year. CDCs = cardiosphere-derived cells; EDV = end-diastolic volume; EF = ejection fraction; ESV = end-systolic volume; LV = left ventricle.
(A) Scatterplot showing the natural relationship between scar size and left ventricular ejection fraction ∼5 months post-myocardial infarction (circles). Each cross symbol represents the mean values (at the intersection of the vertical and horizontal bars [obtained from all patients with magnetic resonance imaging measurements]), whereas the width of each bar equals ±SEM of scar size and left ventricular ejection fraction of CADUCEUS patients at baseline, 6 months, and 1 year; the crosses are superimposed onto the scatterplot showing prior data from post-myocardial infarction patients with variable scar sizes. The changes in left ventricular ejection fraction in CDC-treated subjects are consistent with the natural relationship between scar size and ejection fraction in convalescent myocardial infarction, whereas the changes in left ventricular ejection fraction in controls fall within the margins of variability. (B) Changes in end-diastolic volume from baseline to 1 year. (C) Changes in end-systolic volume from baseline to 1 year. CDCs = cardiosphere-derived cells; EDV = end-diastolic volume; EF = ejection fraction; ESV = end-systolic volume; LV = left ventricle.

Other observations included safety assessments. When the number of adverse events between the control group and CDC-receiving group were measured, there were no differences between the two groups. The patients in the CDC-receiving group were more likely to be hospitalized and had transient cases of fast heartbeats, and there was also one death in this group. However the incidence of these events were not statistically different from the control group.

From these assessments, it is clear that the CDC treatments are safe, and decreased the scar size and regional function of infarcted heart muscle. From these results, the researchers state that “These findings motivate the further exploration of CDCs in future clinical studies.

Modified RNA Induces Vascular Regeneration After a Heart Attack


Regenerating the heart after a heart attack remains one of the Holy Grails of regenerative medicine. It is a daunting task. Even though text books may say, “the heart is just a pump,” this pump has a lot of tricks up its sleeve.

Stem cell treatments can certainly improve the structure and function of the heart after a heart attack, but getting the heart back to where it was before the heart attack is a whole different ball game. To truly regenerate, the heart, the organ or parts of it need to be reprogrammed to a time when the heart could regenerate itself. If that sounds difficult, it’s because it is. But some recent work suggests that it might at least partially possible.

Kenneth Chien and his colleagues from the Department of Stem Cell Biology and Regenerative Medicine at Harvard University have published a terrific paper in the journal Nature Biotechnology that tries to turn back to clock of the heart to augment its regenerative capabilities.

The outermost layer of the heart that surrounds the heart muscle is a layer called the “epicardium.”

epicardiumIn the epicardium are epicardial heart progenitors and these cells are activated within 48 hours after a heart attack in the mouse.  In the fetal heart, epicardial heart progenitors migrate into the heart and differentiate into heart muscle, blood vessels and smooth muscles.  In adults, these cells remain on the surface of the heart and differentiate largely into fibroblasts.  When it comes to regenerative medicine, can we take adult epicardial cells and reprogram them to act like fetal epicardial heart progenitors?

A few experiments have suggested that we can.  In 2011, Smart and others used a small peptide called thymosin β4 to reprogram epicardial cells in mice to form heart muscle and other heart-specific tissues.  Even though the reprogramming was not terribly robust, Smart and others convincingly showed that it was real (Nature 474,640–644).

The Chien group used modified RNA molecules made with unusual nucleotides that encoded the protein vascular endothelial growth factor-A (VEGF-A) to reprogram the epicardium of mice.  VEGF-A is very good and reprogramming the epicardium, and this modified RNA technique does not induce and immune response the way injecting DNA does and the RNA causes bursts of VEGF-A activity that efficiently reprograms the epicardium.

After giving mice heart attacks, Chien and others injected the VEGF-A modified RNAs into the border of the infarcted area of the heart. The modified RNAs induced new gene expression that is normally seen during the establishment of blood vessels.  VEGF-A expression was elevated for up to 6 days after the injections, and animals that had their hearts injected with modified VEGF-A RNA had smaller scars in their hearts, less cell death, and greater tissue volume in their hearts than animals that received either injections of VEGF-A DNA, buffer, or modified RNA that expressed a glowing protein.  Also, the effects of the modified VEGF-A RNA could be abrogated with co-administrating the drug Avastin, which is an antagonist of VEGF-A

Tests with cultured heart cells showed that VEGF-A modified RNA induced blood vessel-specific genes.  These inductions were sensitive to drugs that blocked the VEGF-A receptor, which shows that it is indeed the VEGF-A protein that is inducing these trends.  Finally, a heart muscle gene, Tnnt2 is also induced by the modified VEGF-A RNA.  When the efficacy of the modified VEGF-A RNA was tested in living animals, if was clear that the most numerous cells induced by the modified VEGF-A RNA was endothelial cells, which line blood vessels, followed by smooth muscle cells, and then by heart muscle cells.

Thus, the growth factor VEGF-A can signal to epicardial heart progenitor cells to heal the heart after a heart attack in mice.  It works through the VEGF-A receptor (KDR), and it induces epicardial derived cells (EPDCs) to differentiate into blood vessels, heart muscle cells, and smooth muscle cells, all of which are required to heal the heart.  If VEGF-A signaling can be used to augment heart healing after a heart attack, it might provide a new strategy for healing the heart after a heart attack in a manner that helps the heart heal itself from the inside rather than placing something from the outside into it.

Transplanted Human Umbilical Cord Blood Cells Improved Long-Term Heart Muscle Structure and Function in Rats After a Heart Attack


Jianyi Zhang, from the University of Minnesota Health Science Center, in Minneapolis, Minnesota and his co-workers have shown that the transplantation of human umbilical cord blood cells into the rat hearts after a heart attack experience long-term effects that are not observed in the control animals that did not receive the stem cells. Furthermore, none of these laboratory animals required immunosuppressive therapy. The study is scheduled to be published in the journal Cell Transplantation.

“Myocardial infarction induced by coronary artery disease is one of the major causes of heart attack,” said Dr. Zhang. “Because of the loss of viable myocardium after an MI, the heart works under elevated wall stress, which results in progressive myocardial hypertrophy and left ventricular dilation that leads to heart failure. We investigated the long-term effects of stem cell therapy using human non-hematopoietic umbilical cord blood stem cells (nh-UCBCs). These cells have previously exhibited neuro-restorative effects in a rodent model of ischemic brain injury in terms of improved LV function and myocardial fiber structure, the three-dimensional architecture of which make the heart an efficient pump.”

According to Zhang and his co-authors, stem cell researchers have intently examined the ability of stem cells to regenerate and heal damaged heart tissue. Many laboratories all over the world have employed different types of stem cells, different animal models, and distinct modes of stem cell delivery into the heart tissue, and different stem cell doses. All of these studies have produced varying levels of improvement of left ventricular function. Zhang and others also note that, for the most part, the underlying mechanisms by which implanted stem cells improve heart function are “poorly understood and that the overall regeneration of heart muscle cells is modest at best.

In order to investigate the heart’s remodeling processes and to characterize the alterations in cardiac fiber architecture, Zhang’s team used diffusion tensor MRI (DTMRI), which has been previously used to study heart muscle fiber structure in both humans and animals. Most previous studies have concentrated on the short-term effects of umbilical cord blood cells (UCBCs) on damaged heart muscles. Fortunately, this study, which examined the long-term effects of UCBCs, not only demonstrated evidence of significantly improved heart function in treated rats, but also showed evidence of delay and prevention of myocardial fiber structural remodeling. Keep in mind that such alterations in heart muscle fiber structure could have resulted in heart failure.

When compared to the age-matched but untreated rat hearts that had suffered a heart attack, the regional heart muscle function of non-hematopoietic UCBC-treated hearts was significantly improved and the preserved myocardial fiber structure seems to have served as an “underlying mechanism for the observed function improvements.”

“Our data demonstrate that nh-UCBC treatment preserves myocardial fiber structure that supports the improved LV regional and chamber function,” concluded the researchers.

“This study provides evidence that UCBCs could be a potential therapy with long-term benefits for MI” said Dr. Amit N. Patel, director of cardiovascular regenerative medicine at the University of Utah and section editor for Cell Transplantation. “Preservation of the myocardial fiber structure is an important step towards finding an effective therapy for MIs”

See: Chen, Y.; Ye, L.; Zhong, J.; Li, X.; Yan, C.; Chandler, M. P.; Calvin, S.; Xiao, F.; Negia, M.; Low, W. C.; Zhang, J.; Yu, X. The Structural Basis of Functional Improvement in Response to Human Umbilical Cord Blood Stem Cell Transplantation . Cell Transplant. Appeared or available online: December 10, 2013.

When Is the Best Time to Treat Heart Attack Patients With Stem Cells?


Several preclinical trials in laboratory animals and clinical trials have definitively demonstrated the efficacy of stem cell treatments after a heart attack. However, these same studies have left several question largely unresolved. For example, when is the best time to treat acute heart attack patients? What is the appropriate stem cell dose? What is the best way to administer these stem cells? Is it better to use a patient’s own stem cells or stem cells from someone else?

A recent clinical trial from Soochow University in Suzhou, China has addressed the question of when to treat heart attack patients. Published in the Life Sciences section of the journal Science China, Yi Huan Chen and Xiao Mei Teng and their colleagues in the laboratory of Zen Ya Shen administered bone marrow-derived mesenchymal stromal cells at different times after a heart attack. Their study also examined the effects of mesenchymal stem cells transplants at different times after a heart attack in Taihu Meishan pigs. This combination of preclinical and clinical studies makes this paper a very powerful piece of research indeed.

The results of the clinical trial came from 42 heart attack patients who were treated 3 hours after suffering a heart attack, or 1 day, 3 days, 2 weeks or 4 weeks after a heart attack. The patients were evaluated with echocardiogram to ascertain heart function and magnetic resonance imaging of the heart to determine the size of the heart scar, the thickness of the heart wall, and the amount of blood pumped per heart beat (stroke volume).

When the data were complied and analyzed, patients who received their stem cell transplants 2-4 weeks after their heart attacks fared better than the other groups. The heart function improved substantially and the size of the infarct shrank the most. 4 weeks was better than 2 weeks,

The animal studies showed very similar results.

Eight patients were selected to receive additional stem cell transplants. These patients showed even greater improvements in heart function (ejection fraction improved to an average of 51.9% s opposed to 39.3% for the controls).

These results show that 2-4 weeks constitutes the optimal window for stem cell transplantation. If the transplant is given too early, then the environment of he heart is simply too hostile to support the survival of the stem cells. However, if the transplant is performed too late, the heart has already experiences a large amount of cell death, and a stem cell treatment might be superfluous. Instead 2-4 weeks appears to be the “sweet spot” when the heart is hospitable enough to support the survival of the transplanted stem cells and benefit from their healing properties. Also, this paper shows that multiple stem cell transplants a two different times to convey additional benefits, and should be considered under certain conditions.