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An Interview with Daniel Aberdam

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A personal insight from the Head of this month’s Featured Lab on the Stem Cells Portal, Daniel Aberdam.

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I was born in Paris and completed my first degrees in life sciences at Pierre and Marie Curie University (Paris, France). During the last year of my BSc studies I met Prof. Daniel Blangy, a fantastic teacher who taught us genetics and molecular biology. We all felt that the lectures of this remarkable virologist were too short and I immediately knew that molecular biology would be my field of research. With his advice, I moved to Israel for a PhD at the Weizmann Institute under the supervision of Prof. Leo Sachs on homeotic genes and cancer. I then moved to Nice (France) for postdoctoral training in the department of Dermatology directed by Prof. J.P. Ortonne. In 1995, I got a tenure position at the INSERM institute. My scientific interests turned to epidermal gene regulation with the identification of skin specific promoters. More recently, my group has focused on skin physiopathology using embryonic stem cells as cellular model. I currently hold the positions of INSERM Director of Research at the University of Nice (France) and Visiting Professor at the TECHNION (Israel). Since 2006, I am the director of an associated INSERM/TECHNION laboratory located at the Israel Institute of Technology (TECHNION) where we are developing projects linked to pluripotent stem cells as cellular models for physiopathologies’ -Daniel Aberdam

 

An Interview with Daniel Aberdam

By Carla Mellough

 

What was your original motivation for pursing a career in stem cell research?

My direct involvement in the stem cell field came late during my career. After my PhD at the Weizmann Institute on the oncogenic potential of homeotic genes, I devoted my postdoctoral training to skin physiopathology in Nice. We discovered the genes responsible for severe human skin diseases that allowed the first antenatal diagnosis for lethal junctional epidermaolysis bullosa syndromes. Then, I got a position as Director of Research at INSERM. Later I realized that, although the transgenic technology is particularly powerful to identify functions of genes during development, most of the congenital skin diseases (and many other pathologies) lack cellular models to recapitulate in vitro the main steps of human embryonic development. In 2002, I decided to switch our research to the stem cell field and we turned to embryonic stem (ES) cell technology. It is paradoxal that it took me a decade to enter the stem cell field while my PhD mentor, Prof. Leo Sachs, was a pioneer in that field. Among many achievements, he discovered and identified the colony-stimulating factors and some interleukins that control the viability and growth of hematopoietic stem cells and their development into different types of mature blood cells. His discoveries provided the basis for prenatal diagnosis of human diseases and the treatment of leukemia.

 

Your laboratory has developed a unique cellular model that recapitulates embryonic development of epidermis and skin appendages that could potentially be used as a disease model, for toxicology screening or for cell therapy in patients. In your experience, what appear to be the main differences between hESC-derived skin’ and epidermis in situ? What do you think are the main factors which mediate these differences?

In 2003, we designed a robust protocol to differentiate murine ES cells into skin. Remarkably, this differentiation process recapitulates the crosstalk that occurs in utero between the mesoderm and the ectoderm for the formation of the embryonic skin. It allows the characterization of genes and signalling pathways involved in these critical steps and their involvement in skin defects found in patients affected by congenital disorders, like ectodermal dysplasia syndromes. Recently, we used reprogramming technology to derivate pluripotent stem cells (iPS) from patients affected by several skin and mental diseases, for which no adequate cellular models are available. In our pioneer study we demonstrated the ability of murine ES cells to produce skin in an organotypic reconstitution assay, but the differentiation efficiency was quite low. Our purpose was to design an in vitro cellular model to study the main steps of normal and pathological skin development. Since 2003, few protocols have been published on the differentiation of human ES cells into skin cells (keratinocytes). Among them, only two have reported the production of epidermal cells with high efficiency (S. Palecek and G. Waksman's groups) and only the latter, applying our murine protocol to human cells, has demonstrated their ability to form a 3D pluristratified epidermis that could be grafted onto mice. However, from our own and other studies, such keratinocytes derived from human ES cells do not behave as adult epidermal cells. For instance, the adhesion molecules (E-cadherin network for example) that allows strong cell-cell cohesion within epidermal colonies is not fully activated. Furthermore, the cells do not grow as primary somatic epidermal cells and their obtention is a dramatically slow process (50-60 days). More importantly, they do not form skin appendages that are mandatory for optimal lubrification (sebaceous glands), thermoregulation (sweat glands) and tissue renewal (hair follicles). For all these reasons, they do not represent (for the moment) an advantage over autologous somatic cells that are routinely used around the world to save severe burn patients. Finally, these cells remain allogenic and there is no experimental evidence today that they will be less immunogenic following transplantation than adult allogenic epidermal cells. No study has compared the transcriptome/proteome of the somatic versus embryonic epidermal cells but our unpublished data strongly suggest major differences. In brief, and in contrary to what was unwisely declared last year, we are still far from the usage of pluripotent stem cells for human skin cell therapy. However, our major interest in the use of pluripotent stem cells still concerns basic research. The cellular models we have designed could be powerful as alternative of animal models for cell toxicity, high throughput screening of drugs and cosmetics related to the skin and cornea.

  

Of the possible applications of your work, which do you think is the most achievable? How quickly do you think cell therapy could be transferred to the clinic? Which patients in your opinion are the best candidates in which to test such therapy?

Even if pluripotent stem cells turn out to be unsuitable for skin cell therapy, they might be of interest for skin gene therapy. Dystrophic (DEB) and junctional epidermolysis bullosa (JEB) are severe skin diseases for which no treatment is currently available. One JEB gene therapy assay has been reported by M. de Luca's team in 2006 but was stopped because of the use of retroviruses that could integrate randomly and activate oncogenes. A novel approach is currently being considered through the reprogramming of patient fibroblasts into iPS cells that can undergo homologous recombination (like ES cells) to correct the mutation without insertion of foreign DNA fragments. The challenge is then to produce a full thickness skin from the corrected iPS for autologous transplantation. Several laboratories, including ours, are working on this issue from which patients could benefit in the next 10 years. In addition, we recently produced corneal epithelium from human pluripotent stem cells that could be a relevant alternative for both cell therapy (cornea loss and limbal deficiencies) and an in vitro cellular model for cell toxicity and drug design.

 

What is your understanding of successful research?

The trivial answer is to demonstrate experimentally the validity of the original hypothesis that leads to a breakthrough in the field and, because our career depends on it, a high impact factor publication. The real fun is complete when the right experiments have been designed which allow us to clarify the molecular basis for the original observation. It could be also an unexpected discovery arising from the observation of a strange phenomenon. Of course, translation to clinical implications would be the best achievement.

 

Can you reflect on what you feel was one of the most important experiences or defining moments in your education, career, or life that has contributed to your success as a researcher? How do you think this has this affected your work and/or career?

I can think about two major milestones: first, I was lucky to have Prof. Leo Sachs as my PhD supervisor. This remarkable researcher taught me to enjoy research, to address new (provocative) questions and to try to answer them with rigor and obstinacy. My second founder experience was during my postdoctoral training when we first discovered the genes responsible for the JEB geneodermatosis. It allowed us to provide a prenatal diagnosis to families already concerned by an affected child. It prevented the birth of babies condemned to death several months after delivery.

 

What do you feel is the most challenging aspect of your job?

To transmit scientific curiosity, enthusiasm and persistence to the new students and young postdoc fellows. Young scientists must enjoy daily the luck of performing original experiments and the positive stress before getting the result. To be open to new disciplines, new technologies.

 

How important is a collaborative approach in your research and how multidisciplinary has this been/is this becoming, in your experience?

Modern research needs multidisciplinary experimental approaches that require active collaborations. The European Union funding, for which labs must apply as collaborative networks, gives a good opportunity to initiate active and productive collaborations.

 

What would your words of advice be to young researchers trying to find their way in the stem cell field and obtain funding in this highly competitive field and under the current economic climate? It seems that the barrier is always being raised in order to achieve funding. What effect do you think this has on the research that is being undertaken and the way in which it is conducted?

At the beginning of a career, a young researcher must try to develop in parallel one project in a field where major funding could be raised and a second project more risky but from which more satisfaction can be obtained. It is also becoming more and more obvious that the choice of research project is somehow influenced by the field where more funding could be raised.

 

How do you think the current funding situation will affect the progression of stem cell research in the short and/or long term?

This is one of most problematic issues in the sciences in general and certainly in the stem cell field. We are facing huge difficulties to publish in top journals, even with original, good and complete studies. The affiliation of the laboratory, its geographic location and the marketing efforts are parameters as important as the scientific quality of the submitted work. It takes more and more time for a work to be published and this has an important impact on the motivation of the young members in the lab. Moreover, we depend on funding that is more and more difficult to raise. Particularly in Europe, there is an increasing tendency to call for projects directly linked to preclinical trials, biotechnology, cancer or diseases. Unfortunately, there is no (or few limited) specific call in Europe devoted to Stem cell research. As a consequence, it becomes more and more difficult to develop fundamental basic research, although it remains our primary motivation and interest.

 

There has been a huge shift in public thinking about the use of stem cells for research and to ameliorate human disease. In your opinion, what are the main barriers that still remain for the clinical translation of hESC? How do you foresee these being overcome?

For some limited applications, mainly cardiac failure and neurodegenerative diseases, human ES cells have been already shown on primate models to be feasible and could bring a real benefit for cell therapy. This is particularly true when no alternative from somatic adult cells is available. The main limitation of the use of human ES cells is to get rid of any contaminated undifferentiated cells before transplantation to avoid teratoma formation. For cardiac therapy, one French group leaded by Michel Pucéat and Philippe Menashé identified a surface marker CD15 specific for cardiac progenitors that allow for purification by cell-sorting of committed cells. They have already demonstrated that such isolated cells incorporate and function well within the host primate heart without any formation of teratomae from the committed ES cells. The translation to humans could be fast, within the next two years. Obviously, the immunogenic status of these cells should be considered as allogenic cells and will probably require immunosuppressant drugs, at least at the beginning. The third limitation remains linked to the psychological and ethical hesitation to use embryonic cells for human therapy. As discussed below, the translation of the accumulated knowledge on human ES cells to iPS could resolve this issue.

 

A number of recent articles implicate that induced pluripotent stem cells (iPSC) may be more dissimilar to hESCs than was initially thought and thus cast some doubt over the applicability of iPSC for the treatment of human disease. In your opinion, how important do you think these differences are?

From the recent publications, it seems that iPS cell lines could be heterogenous and sometimes dissimilar to human ES cells, mainly because of their relative state of reprogramming. Therefore, to avoid the use of "pseudo" iPS cell lines, standard methods need to be developed to define their true identify as pluripotent self renewing cells. Moreover, it has become apparent that epigenetic imprinting of the original cell type used for reprogramming are kept by iPS cells. Apparently this is lost after passaging of the iPS cell lines. The latter issue, which has not yet been sufficiently studied is the ageing of iPS cells lines derived from old somatic cells. Have they already accumulated the patient mutations that could make these iPS more susceptible to tumorigenesis, to premature senescence/aging? Therefore, before thinking about their use for cell therapy, iPS cells need to be studied in parallel with human ES cells much more closely.

 

In your opinion, what do you consider to be the most important advance in stem cell research over the past 5 years?

Undoubtedly, Yamanaka's discovery that somatic cells can be converted so easily into pluripotent ES-like cells. It paves the way for the design of unlimited cellular models for human pathologies, in the realistic hope to identify new drugs, to avoid animal use for cell toxicity tests and of course as cellular sources for cell and gene therapies.

 

What are your hopes for the future stem cell research and clinical translation in your specialist area?

That alternative cell and gene therapy will be available in the next two decades for patients suffering from severe epidermolysis bullosa, maybe from pluripotent stem cells.

 

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Figure 1. Skin reconstituted from embryonic stem cells that have been simultaneously coaxed to both epidermal and fibroblastic cell fates.

 

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Figure 2. Ectodermal progenitor derived from embryonic stem cells that were transfected with DNp63 (green) construct expresses de novo epidermal cytokeratin K14 (red).

 

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Figure 3. Ectodermal progenitors derived from embryonic stem cells that were transfected with pax-6 (red) construct express de novo corneal cytokeratin K12 (green).