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Published online before print October 13, 2006
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* Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA; and
Laboratory of Molecular Immunoregulation, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA
1Correspondence: Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD 20892, USA. E-mail: hrosenberg{at}niaid.nih.gov
This manuscript was chosen as a Pivotal Advance because it highlights an important advance in our understanding of the way in which cardiac stem cells may be mobilized. Specifically, Dr. Capogrossi discusses the role of the nuclear binding protein and proinflammatory cytokine, high mobility group box 1 (HMGB1) protein, in initiating activation and differentiation of endogenous cardiac stem cells in a mouse model of myocardial infarction [1 ]. The capacity of HMGB1 to promote the development of mouse cardiomyocytes and initiate repair of myocardial infarction is quite remarkable.
Dr. Capogrossi, you have an extensive publication record focusing on cardiac function and cardiac cell biology. Where did you get the inspiration to look at HMGB1 as a regenerative agent?
MCC: The possibility of evaluating HMGB1 as a regenerative and proliferative agent in the myocardium was first suggested by my former fellow, Dr. Roberta Palumbo. She had already performed a series of experiments with my close collaborator, Dr. Marco Bianchi, in which they demonstrated that HMGB1 induced migration and proliferation of blood vessel mesangioblasts, which are blood vessel stem cells [2 ]. Evaluating the effects of HMGB1 on myocardial stem cells seemed like an obvious next step for all of us.
Is HMGB1 the only cytokine with cardiac stem cell (CSC)-activating or regenerative powers? Are there others?
MCC: There are definitely other cytokines that are already known to modulate cardiac stem cell function. Several groups have explored the role of hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1) in mobilizing cardiac stem cells [3 4 5 ]. Recently, Mark Sussman and his colleagues [6 , 7 ] have explored the Akt-mediated signaling pathway vis à vis cardiac stem cell proliferation. There are certainly other factors remaining to be discovered.
Interestingly, the mechanism by which HMGB1 works is not yet clear. Our current working hypothesis is that it functions by interfering with pro-apoptotic pathways.
In this work, you feature primarily mouse CSCs. Have human CSCs been characterized? How similar are mouse and human CSCs? Are mice the best animal model for studying CSC biology?
MCC: Human CSCs can be obtained fairly readily from cardiac surgery specimens, and they have been characterized to a very limited extent. They grow slowly, and it is not clear how to get them to differentiate, so they are difficult to work with. As such, it is too early to comment on similarities and differences between mouse and human CSCs, as too little is known about adult human CSCs. The best system for this sort of work—maybe monkeys would have the advantage of genetic similarity to humans, but of course this becomes impractical and very expensive, and would limit research to only a few labs. Pigs are likewise impractical for most groups, and there are very few sophisticated molecular tools available for working in pigs. Given this, it is clear that the mice and humans will continue to be primary model systems, and will be the source of many basic science discoveries in this field.
In your manuscript, you discuss HMGB1 as a potential clinical therapy, possibly in association with myocardial infarction. What do you see as the major hurdles that need to be overcome scientifically and practically before HMGB1 therapy becomes a reality?
MCC: Certainly we would like to see HMGB1 develop into a useful clinical therapy. However, before this happens, we need to show that HMGB1-stimulated myocytes derived from CSCs will grow to large size and gain contractility. Cardiac ventricles comprised of HMGB1-treated cells need to be strong and not undergo inappropriate dilation in response to elevated intracardiac pressures.
Interestingly, one major advantage of the adult cardiac stem cell population is that one can access them in situ. In our current experimental protocols, CSCs are removed, cultured, and returned to animals, a process which takes several months. Ultimately, we envision a situation in which HMGB1 could be administered to patients during an acute event, perhaps directly to the myocardium during infarction. With this scenario, one might be able to begin to regenerate healthy heart tissue from the first possible moment.
Will the use of HMGB1 and other activators perhaps circumvent the need for stem cell therapy?
MCC: I regard HMGB1 and any other drug or molecule acting on resident stem cells in vivo as a form of stem cell therapy. In other words, I would not limit the definition of stem cell therapy to those interventions in which stem cells are removed from the organism or patient, manipulated ex vivo and then re-injected into the patient. Any intervention that relies on stem cell "activation" and use for therapeutic purposes fits into the definition of stem cell therapy.
On a more personal note, can you tell the readers of JLB a bit about yourself and your scientific background?
MCC: After graduating in 1975 with a degree in medicine from University of Rome "La Sapienza," I worked for one and a half years as an Endocrine Fellow and subsequently I spent three years in the Internal Medicine Residency at Emory University in Atlanta, Georgia. To expedite US Citizenship papers, I spent a year as a staff physician in southern Georgia, providing medical care to underserved people. I met many dedicated physicians who worked tirelessly to improve the quality of life for their patients, and to this day, this remains one of the most moving experiences of my life.
From there, I moved in 1982 to the National Institute of Aging, NIH, Laboratory of Cardiovascular Sciences in Baltimore, Maryland; I worked as Medical Staff Fellow until 1984 and for the subsequent three years I was a Cardiology Fellow at The Johns Hopkins University in a combined JHU/NIH program. In 1987, I was promoted to tenured NIH scientist and I was granted a faculty position at JHU, in Cardiology.
In 1996, I returned to Italy to direct Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata (IDI)-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy, and in 2001, began a close tie with a second laboratory, Laboratorio di Biologia Vascolare e Terapia Genica Centro Cardiologico Fondazione "I. Monzino," IRCCS, Milan, Italy. I remain in this position now, and enjoy many fruitful collaborations with scientists at these institutions.
In the US there is currently a ban on federal funding for human embryonic stem cell research. What do you see as the outcome of this policy worldwide?
MCC: To discuss embryonic stem cell research, one first needs to set the terms regarding ethical issues. Simply put, there are some people who believe that using a human embryo for research is homicide, and they will always believe this. And there are others who believe that human embryonic tissue is no different than any other tissue, and they will always believe this opposite view.
But to discuss this subject scientifically, one needs to understand that human embryo research is not a panacea. Even if it was to be approved worldwide, there are many scientific hurdles that need to be overcome before embryonic stems cells become patient-related therapy. One hurdle is that allogeneic embryonic stem cell transplants are likely to induce immune reactions in unrelated recipients. Similarly, embryonic stem cells have a tendency to form tumors. Harnessing this technology will not be easy, nor will it be straightforward.
On the other hand, there is much to be learned from the study of adult stem cell populations. Adult stem cells harvested from specific somatic tissues might be manipulated and reintroduced into the same individual, thus reducing the possibility of rejection. Taken one step further, adult stem cells might ultimately be differentiated and developed in situ without the need for external manipulation at all. And of course, studies relating to adult stem cells are not burdened with the same ethical dilemmas as those facing research on human embryonic stem cells.
At the same time, there is a lot that can be learned from the study of mouse embryonic stem cells. There are economically developed, scientifically advanced countries that are funding human embryonic stem cell research at this time. If embryonic stem cells do in fact become useful tools in the treatment of disease, governments in the US and in other countries will have to face strong public pressure to consider these options. Otherwise, people of sufficient means will of course go elsewhere to get needed treatments.
Perhaps, given the ethical concerns, the US might consider investing more heavily in adult stem cell research?
Is there anything else that you’d like to share with the readers about your manuscript, your life in science, or any specific any advice to younger students considering a career in basic research?
MCC: Science is a wonderful way to express one’s creativity, to be like an artist, just as someone who paints or composes music. You can only do scientific research if you really want to do so and if you enjoy it very much, it’s really more of a passion, almost like falling in love. After all, you will find that you work harder than most, it is difficult to find jobs, and the jobs that you do find will pay you less than most others, and this may all cause a strain on your personal life. There is no reason to be in science other than passion for the work.
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