Distinguished Speaker Series | Majlinda Lako, PhD

Research activities

The primary approach in our research group is to use pluripotent stem cells to mimic human development using in vitro model systems. The experience of deriving human embryonic stem cells in 2003, led to a broader interest in the pluripotent stem cell biology, which enabled my team to describe for the first time the difference in transcriptional profile and signalling pathways between human and mouse embryonic stem cells and the intrinsic link between maintenance of pluripotency and cell cycle control. Pursuing novel differentiation methods and mimicking embryonic development, we were able to generate long-term engrafting hematopoietic stem cells, a finding of great interest in the field, which was published in Cell Stem Cells and accompanied by several press releases.

Following Yamanaka’s seminar discovery of human induced pluripotent stem cells (hiPSCs), our group was one of the first in UK and EU to embrace the technique and to use it successfully for studies of reprogramming, differentiation and disease modelling. With this expertise, my group was an important contributor to the IMI1 funded hiPSC initiative “STEMBANCC”, which involved cooperation of multiple EU academic and large pharma companies. During this project, we group derived and characterised >450 patient specific hiPSCs, which are currently used worldwide for studies of neurodegeneration and drug discovery.

A cornerstone of our work has been the clinical implementation of stem cell therapy in patients with total and severe limbal stem cell deficiency. Work carried out in my group in collaboration with Prof. Figueiredo has resulted in the development of a GMP compatible culture system for expansion of limbal epithelial cells which have been transplanted into patients with unilateral limbal stem cell (LSC) deficiency.  In the last 15 years, 34 patients have been transplanted successfully and now have a greatly improved vision and quality of life. This is the first example of corneal transplantations in the UK carried out in the absence of any animal derived ingredients. This is the first example of corneal transplantations in the UK carried out in the absence of any animal derived ingredients, which was awarded the orphan designation status by EMA in 2013 (EU/3/13/1168).

Our parallel research programme aims to perfect the differentiation of human pluripotent stem cells to fully laminated retinal structures capable of recapitulating the function of a human retina in vivo. Funded by an ERC Consolidator Award, my group has established an efficient differentiation system to generate optic cup structures which undergo further differentiation to laminated neural retina containing all the retinal cell types. Importantly, these structures are similar not only to the structure of the human retina, they also respond to light stimulation by generating measurable electrophysiological signals, work which has been showcased in EU press releases (https://erc.europa.eu/projects-figures/stories/can-we-grow-artificial-retina). This gives us an unparalleled opportunity to use this technology in constructing models of retinal disease; in this respect, we have been able to establish hiPSCs from patients suffering from both retinitis pigmentosa and AMD, have corrected the faulty genes using Crispr/Cas9 technology and are currently in the process of designing gene therapy trials in collaboration with Prof. Robin Ali at KCL. With the same technology, we have targeted reporter genes to key retinal factors that control rod and cone commitment, thus enabling us to track their emergence during differentiation process, to delineate for the first time their transcriptome at the single cell level and to study their engraftment in degenerate retina, which has led to proof-of-concept early translational studies of human photoreceptor transplants in animal models of advanced retinal degeneration.

In the last three years and funded by MRC and BBSRC UK, our research team has generated single cell maps of adult and developing human cornea and retina in normal steady state and disease conditions. The publication reporting the first integrated single cell atlas of human cornea was published by the prestigious  Ocular Surface journal and was the subject of a BBC5 live interview with Naga Munchetty on the 19^{th of} March 2021. These data have been extremely useful for assessing the SARS-CoV-2 entry genes in the upper airways and ocular surface, an effort, which has enabled us to interact closely and share data freely with all the groups working under the Human Cell Atlas initiative. This joint work is featured in five recent manuscripts, published in Nature Medicine, Circulation, Ocular Surface, and Stem Cells Translational Medicine and several press releases (https://www.ncl.ac.uk/press/articles/latest/2020/04/nosecellscovid-19/). In recognition of these efforts, we were awarded BBSRC funding to further explore the SARS-CoV-2 infection of the ocular surface.