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2011 Winner - Dr. Meyer-Blazejewska



What Drives a Young Investigator? An Interview with Dr. Ewa Meyer-Blazejewska

Late last year STEM CELLS presented its 2011 Young Investigator Award to Dr. Ewa Meyer-Blazejewska for her research into how stem cells from harvested hair follicles can be used to treat limbal stem cell deficiency (LSCD).

The $10,000 prize is awarded annually to a young scientist whose paper is judged to be of worldwide significance by a global jury. Dr. Meyer-Blazejewska’s paper, “From Hair to Cornea: Toward the Therapeutic Use of Hair Follicle-Derived Stem Cells in the Treatment of Limbal Stem Cell Deficiency,”was published in STEM CELLS in January 2011.

LSCD is caused by the loss or dysfunction of limbal stem cells. As a result, the cornea clouds up and develops a rough surface, causing its victims persistent pain and severe visual impairment. The condition often affects young adults; by far, its most common cause is chemical burns.

Current treatments focus on harvesting limbal cells from a patient’s healthy eye or from cadavers. However, in her pioneering research, Dr. Meyer-Blazejewska, a scientist at the University of Erlangen-Nürnberg, in Germany, considered the use of stem cells taken from hair follicles to reconstruct damaged tissue for patients who suffer from LSCD in both eyes.

Dr. Meyer-Blazejewska’s team demonstrated that in the right microenvironment, these stem cells do have the capacity for cellular differentiation. The study showed an 80 percent rate of differentiation in mouse eyes following a cell transplant, highlighting the promising therapeutic potential of hair follicle-derived stem cells.

We caught up recently with Dr. Meyer-Blazejewska and asked her to share more information with STEM CELLS’ readers on her study and to provide an update on her career.

What hypothesis were you testing in the research described in your paper?

Finding a new source for autologous adult stem cells for treatment of LSCD is one of our main research focuses. In our review of the literature we came across the hair follicle and found it to be a very potent source of diverse stem cell populations that possess a high degree of plasticity and are able to be reprogrammed into other cell types.

Our objective was to reprogram hair follicle stem cells into a corneal epithelial cell phenotype.

Taken together, it can be said that transplantation of autologous limbal stem cells is the most effective therapy thus far to treat LSCD, but it is only applicable to patients unilaterally affected. Transplantation of cadaveric tissue is also possible and currently being employed, but it is limited by a low number of donors, which means long waiting times for patients and the need of immunosuppresive therapy as the risk of transplant rejection in such cases is much higher.

There is still no optimal therapy for bilateral LSCD, which highlights the need for an autologous stem cell source that will be more beneficial to patients than is currently available.

Can you explain why this hypothesis was important in stem cell research?

With a greater understanding of the corneal differentiation process, we could optimize the therapeutic approach for the treatment of LSCD through standardization of the procedure, thus making it more efficient. This improvement could be achieved prior to grafting through control of the culture microenvironment and the choice of scaffolding material, with possible growth factor and signal molecule insertion to additionally direct and support transdifferentiation.

The approaches used in our paper will be instrumental for the advancement of research in the areas of stem cell niche, stemness and differentiation, which will aid in the treatment of LSCD as well as other ocular and non-ocular diseases.

Briefly outline the approach you used to test your hypothesis.

First, we isolated hair follicle (HF) bulge cells from the lips of whole body, red tri-transgenic mice and enriched the cells by clonal expansion on a 3T3 feeder cell layer. We could track the progressive clonal growth and expansion of HF-derived, cytokeratin15 (Krt15) positive bulge progenitor cells based on their red fluorescence.

After about three weeks of culture, we detached the clones from the feeder layer and subcultivated them on a transplantable fibrin carrier for approximately seven more days to obtain a confluent epithelial sheet ready for transplantation. Prior to transplantation onto wild type black6 mice, we removed the entire corneal epithelium including the limbus using an Algerbrush and examined the success of the epithelium removal by a fluorescein staining.

We transplanted the HF-derived epithelial sheets with the fibrin gel to the outside and the cells facing the basement membrane. The transplant was fixed with four sutures to the anterior conjunctiva and sclera.

Examination of the sutured eyes immediately after transplantation revealed that the HF bulge-derived stem cells were still intact and expressing the red fluorescent protein, but lacked the green fluorescent protein, which stands for the expression of the corneal differentiation marker Krt12.

Mice were fed doxycycline-enriched chow immediately upon recovery from surgery to monitor Krt12 induction.

Was there a specific methodological technique important to these studies?

Our main goal was to explore the therapeutic potential of murine hair follicle-derived stem cells to treat LSCD using a specialized transgenic mouse model. The transplantations on mice were performed in collaboration with Professor Winston Kao from the Department of Ophthalmology at the University of Cincinnati, who developed the transgenic mouse model that we utilized in our studies.

This transgenic mouse model is comprised of three parts:

1) the first part provides tissue specificity

2) the second allows for induction

3) and the third provides a means to report the differentiation status via a change in color of the cells from red to green.

The whole system is both cornea-specific and inducible, and allows for the detection of Krt12 expressing cells by the presence of green fluorescence.

What does this mean for stem cell biology?

Given the low success rate of the current treatments for patients with bilateral LSCD as well as the unsatisfactory long-term results of using cultivated oral mucosa epithelial cells, there is a need for an alternative stem cell source. Conceptually this paper demonstrates advantages to using hair follicle bulge-derived stem cells in treating bilateral LSCD; namely the stem cells are autologous, readily accessible for isolation, and have the ability to differentiate into cells expressing corneal epithelial markers such as krt12 and pax6 when engrafted onto a corneal microenvironment.

We demonstrated for the first time that, in the right microenvironment, stem cells from hair follicles do have the capacity for cellular differentiation, the process whereby a less specialized cell becomes a more specialized cell type — in this case, cells of the corneal epithelial phenotype. Our results showed an 80 percent rate of differentiation in mouse eyes following a cell transplant, highlighting the promising therapeutic potential of these cells.

Tissue engineering has become a rapidly growing field of research and it is expected to reveal the potential for the application of adult stem cells in different fields of clinical practice.

What hypotheses should be tested next?

We believe that to understand the complex process of corneal epithelium differentiation and to be able to control it ex vivo, we first need to map very accurately the stem cell niche with all the pivotal factors involved in this happening.

We have been working hard on achieving this ambitious goal. Our current research is focused on finding parallels between the hair follicle and limbal stem cell niche, as we already know that both of these tissues can be converted into one another.

This suggests that given the appropriate signals and niche microenvironment, both types of stem cells possess the necessary mechanisms to allow for differentiation into varying cell types.

Why did you select the journal STEM CELLS for your paper?

Because of its eminent reputation in the field of the stem cell research. The papers published in STEM CELLS seem to be selected very carefully, as they are unexceptionally of a great scientific quality. I read every issue of the journal with great interest and every time there are outstanding articles published that I can learn from and which broaden my scientific horizon.

On a more personal note, please tell us a little about you, your education and training. We’d also like to learn why you chose stem cell research and what drives you?

I always have been fascinated by science and research in general. In my spare time I read a lot about translational research and the first successful approaches of stem cell utilization in the different fields of clinical practice.

After my diploma thesis in molecular biology (virology) it was quite obvious to me that I would continue doing research, so I started to look for a doctoral fellow position with a stem cell focus. I was lucky to meet Professor Friedrich Kruse, the director of the Eye Clinic of the University of Erlangen-Nürnberg, whose research focus at the time was the front part of the eye and corneal/limbal stem cells; I have begun to work for him as a doctoral student.

With respect to my motivation, I would say that a great scientific interest and a desire to discover and understand how the human organism works are the main factors that drive me. I really love the feeling when all of a sudden, after a long time of hard work in the lab, the parts of a puzzle start to fit together and you begin to understand the connections hidden thus far.

It is a little bit like being a detective.

Because of my scientific work in the clinical surrounding and in the field of translational research, I discovered my growing interest and passion for medicine and decided to apply for medical school. Since 2010, I have been attending the medical school of the University of Erlangen-Nürnberg and working as a postdoctoral research assistant in its eye clinic.

In the future I hope to continue my existing research while also working as a medical doctor. Personally, this would be a perfect completion of my career.

What impact do you expect the Young Investigator Stem Cells Award to have on your career?

It is a very prestigious award and a great honor to me. It also encourages me in continuing my stem cell research.

This great acknowledgement of my scientific work is certainly very supportive of my future career aspirations.