Stem cells raise new hopes in heart disease

Paul Tunnah interviews Professor Paolo Madeddu

Bristol Heart Institute

The use of stem cell treatments, or regenerative medicine, has hit the headlines more than a few times in recent years. This area of research is an emotive, but often misunderstood one, where concerns over the methods for obtaining stem cells have frequently clouded the significant therapeutic potential they have in treating a range of debilitating diseases.

Recently, there has been an easing of restrictions around stem cell research in the US, perhaps in acceptance of ethical production methods and the clinical potential regenerative medicine holds. Only last week, for instance, California-based Geron announced a pilot clinical study for the use of therapeutic stem cells in patients with serious spinal injuries.

Such treatments also hold significant promise in the treatment of heart disease, one of the most prevalent killers in the West and a major burden to healthcare authorities all over the world. To cut through the myths and find out what is really happening in this space, pharmaphorum caught up with a leading expert on the use of regenerative medicine in cardiovascular disease, Professor Paolo Madeddu, from the Bristol Heart Institute. Listen to the audio interview, or read the highlights below, to understand more about this area and hear his views on where stem cell therapy is heading.

To listen to the full interview, please click on the play button below, with a shortened transcript of key highlights shown in print below.

 

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Interview summary

PT: Thanks for speaking with pharmaphorum today Professor Madeddu. Can you start by telling us about your current role and background?

PM: I am Professor of Cardiovascular Experimental Medicine at the University of Bristol and my focus is to find a new solution for ischaemic diseases, which are caused by blockage of an arterial vessel. To reach this goal my team is using agents that stimulate the formation of new arterial collaterals and we are also using stem cells to regenerate tissues that are starved and damaged by ischaemia.

PT: What’s the link between stem cells and heart disease?

PM: Stem cells are very important for the continuous replacement of cells that die after having completed a cycle, but they are also important when an injury causes many more cells to die, following for instance a heart attack. In very simple animals this repair mechanism is so efficient that the heart can be completely regenerated. Unfortunately, this capacity is less efficient in human patients where cardiac cells that are lost are mostly substituted by a scar. As a consequence the heart cannot pump enough blood to support peripheral tissues, which causes disability and can be lethal for the patient. The hope is that new therapies such as stem cells can far better improve the quality of life, reducing the number of patients that die of a heart attack.

PT: What defines the cell as being a stem cell?

PM: Stem cells are very creative cells and are able to regenerate all the major components of the human body. They maintain themselves by dividing into sister cells, as an alternative they can also undergo an asymmetric division generating one sister cell and one daughter cell. The daughter cell is to generate a cell with specific functions and the first generation daughter cell still has great plasticity – they can give raise to different non-related cells, like cells of the heart skeletal muscle etc. The first generation, or daughter, cells are called progenitor cells, but by subsequent division the progenitor cell population becomes more and more specialised.

 

“Stem cells are very creative cells and are able to regenerate all the major components of the human body.”

 

PT: Where do we find stem cells in the human body and what different roles do they play?

PM: Stem cells are the elements that form the embryo – in fact during development damage to the foetus is usually perfectly repaired without any scar. But the stem cell remains also within organs, in a special environment called a niche, to perform important functions, like the marrow stem cells in bones which continuously produce blood cells. In some organs stem cells are much less represented, like in the heart, where their number is so low in proportion to other cells that for a long time it was impossible to identify them. An Italian scientist, Piero Anversa, convinced other scientists about the existence of such cells in the human heart.

PT: Many people will associate stem cells with controversy over their use in medicine, why are there concerns over this?

PM: There are several concerns. For instance, one ethical controversy is related to the therapeutic use of stem cells derived from human embryos and aborted foetuses. However, foetal cord blood is a potential source of stem cells, but doesn’t raise concerns because it can be collected without any harm to the mother or the newborn. Another concern is the possibility that failure in controlling the growth of stem cells in the human body can lead to transformation into cancerous cells, however current clinical trials using progenitor cells were reassuring here with regard to safety. The final, very important, concern is that many promises from stem cell therapy might not be maintained in clinical practice.

PT: How do stem cells play a role in the broader cardiovascular system?

PM: Stem cells are present in tissue like the heart and also in arteries and veins. These stem cells are able to regenerate the cells of the heart and arteries, but when an injury occurs this low rate repair becomes insufficient. In addition, when a heart attack occurs stem cells migrate towards the injured part of the heart but may not be able to survive this catastrophe. There are other mechanics that then intervene, one is the activation of inflammatory signals that stimulate the bone marrow to increase the production of stem cells, releasing stem cells, progenitor cells and macrophages into circulation. However, they are not competent enough to build new cardiac tissue, they mainly help the heart to rebuild new arterial vessel.

PT: What happens to the protective effects from these stem cells as we age?

PM: Stem cells are not spared by aging. Aging of the stem cell has been defined as a reduction in the capacity to maintain tissue homeostasis and to repair tissues after an injury. Tissue homeostasis and regenerative capacity are nowadays considered to be related to the stem cell pool present in every tissue. For this reason pathological conditions characterised by the altered tissue homeostasis can impact the regenerative capacity, like diabetes, hypertension and arteriosclerosis.

 

“It has been shown that physical exercise, proper diet and refraining from smoking can all help maintain stem cell fitness.”

 

PT: Are there ways in which the healing effects of stem cells can be maintained through later life or perhaps even rejuvenated?

PM: The most recommended way remains to pay attention to the correct lifestyle. It has been shown that physical exercise, proper diet and refraining from smoking can all help maintain stem cell fitness. Some treatments used for the cure of cardiovascular disease, like statins or nitric oxide donors can help too. If a heart attack occurs, the most adopted solution is to provide the patient with supplements of stem cells, the procedure consists of collecting a patient’s bone marrow and then injecting the cells into the patient’s heart. But recent trials are also attempting the transplantation of cells extracted from the patient’s heart through a biopsy, which are expanded in vitro and then re-injected back to the heart. Scientists are also trying to manipulate embryonic stem cells, but this is too premature to be translated into the clinic.

PT: Are there implications here for the pharmaceutical industry?

PM: Sure, regenerative medicine is promising to improve life quality while stabilising healthcare costs, it’s driving the opportunity for companies, especially in the formulation of stem cell therapy production in large stocks for many thousand patients and sold as commercial drugs. Therefore we expect that many more private companies will engage in developing stem cell products for cardiovascular disease.

PT: From a medical perspective people may be more familiar with the concept of introducing new stem cells artificially to help treat disease – tell me a little bit about how that works?

PM: The cells most currently used in clinical trials are from the bone marrow, used for instance to reconstruct the pancreas, the retina, the trachea and the heart. In the case of heart disease their use is to treat heart attack and heart failure, injected through catheter into the coronary artery or by direct puncture of the cardiac wall. Today some 3,000 patients with cardiac problems have received stem cell therapy. In patients treated so far the improvement was estimated to correspond to 3% to 5% of recovery of heart function, percentages that seem quite low, but when added to the benefit from conventional drugs become very important. It is expected that a better result can be obtained with other stem cell types, and with artificial cardiac tissue made with the help of stem cell.

PT: What are the major challenges you see in treating people with stem cells in this way?

PM: This is a new treatment and as for any new treatment we need to be sure that we are adopting the best approach for delivery and selection of patients. There are also important regulatory issues with heart cells, different for those from the bone marrow. Bone marrow cells are used without concern because there is much clinical experience in diseases like cancer, but for other stem cell types the procedures are not yet standardised.

PT: Which are the major companies and organisations that are funding research into this area currently?

PM: Different public and private organisations are keen to fund this research, including the Medical Research Council, the Wellcome Trust and the British Heart Foundation, which is launching a funding campaign next year to support regenerative medicine in the cardiovascular field.

 

“Today some 3,000 patients with cardiac problems have received stem cell therapy.”

 

PT: When do you think we might see these stem cells being used in clinical practice for cardiovascular disease?

PM: It is not possible today to state a precise date. I see progressive application with more patients and the time ranging from 5 to 10 years.

PT: Finally what other areas of stem cell research would you like to see a greater focus on?

PM: Apart from therapy, which remains a major goal of scientists and doctors, as a scientist I am also particularly interested in using stem cells to understand the biology of the human body. This field in the past was mainly limited to embryologists, but today physiologists, pathologists and molecular biologists are working together with doctors toward a better knowledge of how our body works and ultimately stem cells are part of it.

About the interviewee:

Professor Paolo Madeddu has been Chair, Experimental Cardiovascular Medicine at the University of Bristol since 2005 and was elected Head of Regenerative Medicine in 2010. He has around 30 years experience focussed in cardiology and has authored 188 peer-reviewed papers, in addition to being an Associate Editor of Circulation Research, ATVB, Regenerative Medicine and Pharmacology &amp, Therapeutics. Professor Madeddu’s current research focus is on developing more effective therapeutic angiogenesis to treat chronic limb and myocardial ischaemia, in addition to the microvascular effects of diabetes, through the use of stem cell therapies.

For further reading on stem cells readers may wish to visit the Pharmacology &amp, Therapeutics website for details on subscribing. The journal is running a special edition on stem cells. The articles are now available for download at the above website.

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