Our body is covered by tightly packed stratified epithelial tissues which are protecting our organs against external insults (e.g. infections, toxicants, and irradiation). During embryonic development, local molecular cues determine the commitment of the ectoderm into distinct epithelial lineages of the skin and corneal epithelium. In adulthood, the epidermis and corneal epithelium are constantly renewed by stem cells that reside in specialized niche. We are studying the molecular pathways orchestrating these processes in health and disease. Current project are detailed below:

Mechanisms of epithelial development and homeostasis in health and disease

Which region specific signals induce epidermal fate and hair growth and how come skin fate is prevented at the corneal epithelium which is a hairless transparent tissue that covers our eye? Interestingly, the cornea becomes skin-like and opaque in various pathologies that were linked with stem cell dysfunction. A better understanding of these processes may have important clinical relevance to various diseases (e.g. psoriasis, ectodermal dysplasia, aniridia and limbal stem cell deficiency) and may improve our ability to control hair growth/loss, skin aging etc. For reports on our recent work see the following links:

Israeli, French team eyes genetic syndromes cureEye for the Eye: Stem Cell Healing of the Cornea

We address these questions by differentiating induced pluripotent stem (iPS) cells into epidermal or corneal fate using unique protocols that recapitulate embryogenesis. This method is a useful tool for modeling epithelial development in vitro. Moreover, we generate new cellular models for defined genetic disorders (e.g. ectodermal dysplasia syndrome and aniridia) by reprogramming patient somatic cells into iPS cells and exploring their differentiation in vitro. To strengthen our findings, we also use genetic mouse models and we study patients’ tissues. Such models allow the in depth characterization of the molecular circuitry that is affected in disease and provide unique platform for drug screening.

Epithelial stem cells

Epithelial tissues have tremendous regenerative capacity. Indeed, as epidermal and corneal stem cells reside in well-defined niches, they became pioneering examples for cell therapy that has been successfully applied since 1984. Ex vivo expansion of epidermal stem cells that was followed by their transplantation to patients has been shown to be life saving for skin burn patients. Similarly, expansion of corneal stem cells which are located in the limbus restored vision for patients that suffer from corneal diseases. Yet, there is still much to learn in this field. For example, the rapid loss of stem cell self-renewal in the dish is limiting this practice. We therefore believe that for that reason it is important to explore the mechanisms of self-renewal and differentiation of stem cells. What are the molecular cues that preserve stemness and which signals drive stem cell differentiation? How asymmetric cell division of stem cells is controlled? In order to address these questions we study the role of genes on stem cell behavior through in vitro study of stem cells, knockout mice models and by lineage tracing experiments.

Cell therapy

In many cases autologous transplantation of epidermal or corneal stem cells is not possible and allogeneic tissue or cell therapy is applied. iPS cells are promising source for future regenerative medicine. We have previously shown that iPS cells can efficiently differentiate into corneal and epidermal cells. We attempt to further optimize our culture methodology of iPS cell differentiation, genome editing for mutation repair, tissue engineering and grafting of iPS-based therapy in vivo. Another approach that raised much interest is adult stem cell therapy. We focus on studying stem cells in living animals and track their fate and behavior using fluorescent reporter genes, and in combination with advanced culture approach we aim to identify fundamental features of stem cells, mechanisms of stem cell self-renewal and differentiation, and we believe that this knowledge will be harnessed into optimal stem cell therapy.