Trialect

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Stem cell Biology and Regenerative Medicine

Newcastle university

I have 30 years of expertise in human genetics, stem cell biology, and regenerative medicine. I have set up clinical trials and am licensed by regulatory agencies. I am happy to share this experience through this visiting fellowship focusing on stem cells and their application in regenerative medicine.

Main Areas of Interest

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 pluripotent stem cell biology. This enabled my team to describe for the first time the difference in transcriptional profile and signaling pathways between human and mouse embryonic stem cells and the intrinsic link between the 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 seminal discovery of human induced pluripotent stem cells (hiPSCs), our group was one of the first in the UK and EU to embrace the technique and use it successfully for studies of reprogramming, differentiation, and disease modeling. With this expertise, my group was an important contributor to the IMI1-funded hiPSC initiative “STEMBANCC,” which involved the cooperation of multiple EU academic and large pharma companies. During this project, our group derived and characterized over 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 the 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 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, which was awarded 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 into 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 form a laminated neural retina containing all retinal cell types. Importantly, these structures not only resemble the human retina in structure but also respond to light stimulation by generating measurable electrophysiological signals. This work has been showcased in EU press releases (link).

This achievement provides an unparalleled opportunity to use this technology in constructing models of retinal disease. We have established hiPSCs from patients suffering from retinitis pigmentosa and age-related macular degeneration (AMD), corrected the faulty genes using CRISPR/Cas9 technology, and are currently designing gene therapy trials in collaboration with Prof. Robin Ali at King's College London. With the same technology, we have targeted reporter genes to key retinal factors that control rod and cone commitment, enabling us to track their emergence during the differentiation process. This has allowed us to delineate their transcriptome at the single-cell level and study their engraftment in degenerate retinas, leading to proof-of-concept early translational studies of human photoreceptor transplants in animal models of advanced retinal degeneration.

In the last three years, funded by MRC and BBSRC UK, our research team has generated single-cell maps of adult and developing human cornea and retina in both normal steady-state and disease conditions. The publication reporting the first integrated single-cell atlas of the human cornea was published in the prestigious Ocular Surface journal and was the subject of a BBC5 live interview with Naga Munchetty on March 19, 2021. These data have been extremely useful for assessing the expression of SARS-CoV-2 entry genes in the upper airways and ocular surface, enabling us to interact closely and share data freely with 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 (link).

In recognition of these efforts, we were awarded BBSRC funding to further explore SARS-CoV-2 infection of the ocular surface.

Corneal Epithelial Cell Biology and Clinical Applications

Research Focus: Investigating the cellular and molecular mechanisms governing corneal epithelial stem cells, their maintenance, and differentiation.
Clinical Applications: Developing advanced therapeutic strategies for corneal epithelial defects, injuries, and degenerative diseases, including ex vivo expansion and transplantation techniques.

Pluripotent Stem Cells

Derivation: Techniques for the derivation of embryonic and induced pluripotent stem cells (iPSCs) from various sources.
Characterization: Comprehensive profiling of pluripotency markers, genetic stability, and differentiation potential.
Applications: Utilizing pluripotent stem cells to generate retinal and corneal lineages for regenerative medicine and disease modeling.

Gene Editing

Technologies: Application of CRISPR/Cas9, TALENs, and other gene-editing tools for precise genetic modifications.
Research Objectives: Functional genomics studies, creation of knockout/knock-in models, and correction of genetic mutations in retinal and corneal cells.

Gene Therapy

Approaches: Development and optimization of viral (e.g., AAV) and non-viral delivery systems for therapeutic genes targeting retinal and corneal diseases.
Targets: Treating inherited retinal diseases and corneal dystrophies through gene augmentation, silencing, and editing strategies.

Cell Transplantation

Techniques: Isolation, culture, and differentiation of stem cells for transplantation into the retina and cornea.
Applications: Strategies for the transplantation of photoreceptors and retinal pigment epithelial (RPE) cells into degenerative retinas and corneal epithelial cells into damaged corneas.
Integration and Function: Studying the survival, integration, and functional recovery post-transplantation in preclinical models.

Disease Modelling

Stem Cell Models: Using iPSCs and ESCs to generate patient-specific retinal and corneal disease models.
Applications: Modeling inherited retinal diseases, corneal dystrophies, and degenerative conditions for pathophysiological studies and drug testing.
High-throughput Screening: Employing retinal and corneal stem cell-derived models in high-throughput screening platforms for drug discovery.

Drug Discovery

Screening Platforms: Development of robust retinal and corneal stem cell-based assays for drug screening and toxicity testing.
Applications: Identification and validation of novel therapeutic compounds using disease-specific retinal and corneal models.
Pharmacological Studies: Investigating drug mechanisms of action, efficacy, and safety in retinal organoids and corneal cell cultures.

Specialties

Ophthalmology

Stem Cells

Cell Biology

Regenerative Medicine

Molecular Biology

Techniques You Will Learn

Ex Vivo Expansion and Differentiation of Corneal Epithelial Stem Cells: Techniques for growing corneal epithelial stem cells outside the body and inducing their differentiation into mature corneal epithelial cells. Essential for developing cell-based therapies for corneal diseases.

Derivation and Characterisation of Pluripotent Stem Cells: Methods for deriving pluripotent stem cells from various sources and characterizing them to ensure their ability to differentiate into any cell type. This includes assessing genetic stability, pluripotency markers, and differentiation potential.

Differentiation of Pluripotent Stem Cells to Corneal and Retinal Lineages: Protocols for directing pluripotent stem cells to differentiate into specific cell types found in the cornea and retina, crucial for developing therapies for ocular diseases.

AAV Transduction of RPE Cells and Retinal Organoids: Use of adeno-associated virus (AAV) to introduce genetic material into retinal pigment epithelial (RPE) cells and retinal organoids, applied in gene therapy and functional studies.

Vascularisation of Retinal Organoids: Techniques to promote the formation of blood vessels within retinal organoids, enhancing the physiological relevance of these models and allowing the study of diseases affecting retinal vasculature.

Photoreceptor Transplantation into Retinas of Mouse Models with Retinal Degeneration: Methods for transplanting photoreceptor cells into the retinas of mice with retinal degeneration to study cell integration and functional recovery, aiming to restore vision.

Drug Screening Using RPE Cells and Retinal Organoids: Developing and using retinal pigment epithelial cells and retinal organoids to screen for potential drugs. These models provide a relevant environment to test the efficacy and safety of new therapeutic compounds for ocular diseases.

Curriculum

Welcome and Initial Setup

Desk and Equipment Access:

Upon arrival, you will be assigned a personal desk equipped with necessary office supplies.
You will receive login credentials for lab computers and access details for specialized software and databases.
Ensure to familiarize yourself with the lab's safety protocols and emergency procedures.

Orientation and Basic Training

Lab Orientation:

Introduction to lab members and overview of ongoing projects.
Tour of the lab facilities, including cell culture rooms, microscopy suites, and molecular biology workstations.
Overview of lab protocols, data management systems, and ethical guidelines.

Basic Training:

Safety training and certification.
Training on general lab equipment and techniques, such as pipetting, cell culture, and microscopy.
Introduction to the lab's data management system.

Core Techniques and Initial Experiments

Techniques You Can Learn:

Ex Vivo Expansion and Differentiation of Corneal Epithelial Stem Cells: Hands-on training on growing and differentiating corneal epithelial stem cells.
Derivation and Characterisation of Pluripotent Stem Cells: Methods to derive and characterize pluripotent stem cells, including assessments of genetic stability and pluripotency markers.
Differentiation of Pluripotent Stem Cells to Corneal and Retinal Lineages: Protocols for directing stem cells to differentiate into corneal and retinal cell types.

Advanced Techniques and Application

Advanced Techniques:

AAV Transduction of RPE Cells and Retinal Organoids: Training on the use of adeno-associated virus for gene delivery into retinal cells and organoids.
Vascularisation of Retinal Organoids: Techniques to induce blood vessel formation within retinal organoids.
Photoreceptor Transplantation into Retinas of Mouse Models with Retinal Degeneration: Methods for transplanting photoreceptor cells into mouse retinas.

Application to Projects:

Start applying learned techniques to ongoing lab projects.
Work under the supervision of senior researchers to ensure accuracy and reproducibility.

Independent Research and Collaboration

Independent Research:

Design and conduct your own experiments within the scope of the lab’s research areas, such as adult stem cell biology, clinical applications, pluripotent stem cell biology, retinal disease, or gene editing/gene therapy.
Analyze data and troubleshoot experiments with guidance from senior lab members.

Collaboration and Co-Authorship:

Collaborate with lab members on larger projects, contributing to experimental design, data collection, and analysis.
Opportunities for co-authorship on publications if you work in the lab for 12 weeks or more and make significant contributions to the research.

Ongoing Responsibilities and Opportunities

Weekly Lab Meetings:

Present your progress and receive feedback during weekly lab meetings.
Engage in discussions about new research findings and methodologies.

Professional Development:

Attend seminars and workshops offered by the lab and affiliated institutions.
Explore opportunities for further training in specialized techniques and methodologies.

Co-Authorship and Networking:

Potential to co-author research papers and present findings at conferences if you contribute significantly to a project.
Build a professional network by collaborating with other researchers and participating in academic events.

Continuous Learning:

Stay updated with the latest research and advancements in your field of interest.
Seek mentorship and guidance from senior researchers to advance your career in stem cell research and therapy.

Accommodation

Accommodation is facilitated by Newcastle University, depending on availability.
You may also consider options on Airbnb.com for short-term stays.
Our fellows and post-docs can assist you in finding cheaper accommodation or homestay options.

Fees and Program Logistics

This program has the following durations available:

Duration	Fee
2 weeks	$875.00

This program allows Merit Applications. This program allows merit-based applications for virtual and onsite clinical and research programs. If you are successfully awarded under this category, Trialect or the host mentor will cover the tuition fee only. All applications will be evaluated based on merit. Due to the high level of competition, the chances of being selected under the merit category are quite limited.

Who Can Apply

Biomedical sciences and Physicians who have completed their graduation

Host Details

Host Name: Prof. Majlinda Lako

Affiliation: Newcastle university

Address: Newcastle University, Institute of Genetic Medicine, International Centre for Life Central Parkway, Newcastle upon Tyne, NE1 3 BZ, United Kingdom

Website URL: https://www.ncl.ac.uk/medical-sciences/people/profile/majlindalako.html

Disclaimer:It is mandatory that all applicants carry workplace liability insurance, e.g., https://www.protrip-world-liability.com (Erasmus students use this package and typically costs around 5 € per month - please check) in addition to health insurance when you join any of the onsite Trialect partnered fellowships.

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