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Expanded potential stem cells for regenerative medicine, immunotherapy, and biotechnology

   School of Biomedical Sciences

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  Prof P Liu  Applications accepted all year round  Funded PhD Project (Students Worldwide)

About the Project

Embryonic stem cells (ES cells) and induced pluripotent stem cells (iPS cells) are pluripotent and thus hold great promise in regenerative medicine, studying disease mechanisms and drug discovery.

Mouse ES cells are derived from the blastocyst of preimplantation development and contribute to the somatic cell lineages and the germline upon reintroduction to the blastocyst but are excluded from the extraembryonic tissues in the placenta and yolk sac that are derived from the trophectoderm (TE) and the primitive endoderm (PrE). For most mammals, however, establishing ES cell cultures has been challenging. For example, despite many years of intensive efforts by the scientific community, porcine ES cells are still not established. Based on genetic studies of signaling pathways required in preimplantation embryos, we developed a technology to establish stem cells from mouse 4-8 cell stage preimplantation embryos where some embryo cells still retain the development potential to all extraembryonic and embryonic cell lineages (or totipotency features). These new type stem cells are named expanded potential stem cells or EPSCs (Yang et al Nature 2017; Yang et al Nature Protocols 2019). A single EPSC contributes to both the embryo proper and the TE lineages in chimera assay. Trophoblast stem cell (TSC) lines, extraembryonic endoderm stem (XEN) cells, and ESCs could be directly derived from EPSCs in vitro. Molecular analyses of the epigenome and single-cell transcriptome in EPSCs revealed enrichment for blastomere-specific signature and a dynamic DNA methylome.

The EPSC strategy enables establishment of stem cells from multiple mammalian species including pig and human (Gao et al. Nature Cell Biology 2019). Importantly, establishment of porcine EPSCs is the first time that bona fide stem cells are derived from porcine preimplantation embryos. The EPSCs of mammals share similar molecular features and developmental potential (all cell types of extraembyonic as well embryonic lineages). Human and porcine EPSCs are robust in culture and permit efficient genome-editing. The successful generation of EPSCs produces new tools for stem cell fundamental studies, and opens a wealth of avenues for translational research in biotechnology, agriculture, and regenerative medicine.

Project examples:

1. Molecular study of expanded developmental potential in EPSCs. This project aims to dissect the molecular determinants in EPSCs that render these new stem cells the developmental potential to all cell types. These molecular determinants will be investigated in preimplantation embryos for their roles in embryo development, in animal cloning and in cell fate decisions. A range of molecular, single cell genomics, genome-editing and functional assay technologies will be applied and developed in this study. The outcome of this project will be new knowledge of the molecular basis of the early embryo development. Translating this knowledge is expected to improve EPSC culture and to facilitate establishment and application of EPSCs of more mammalian species important in medicine, agriculture and biotechnology.

2. Immune cells from human EPSCs for immunotherapy. Human EPSCs can differentiate to all cell types including somatic cells, such as neurons, cardiomyocytes and immune cells, and placenta trophoblasts. This project will use single cell genomics to dissect the developmental trajectories of human EPSCs to immune cells for efficient generation of immune cells. Genome-editing in human EPSCs will be performed to generate universal stem cells that produce off-the-shelf immune cells for immunotherapy. We previously discovered that inactivating Bcl11b gene in the mouse caused T lymphocyte to lose the T cell identity and to gain the nature killer (NK) cell identity (Li et al. Science 2010). The new killer cells possessed potent killing capacity to eliminate tumour cells in vitro and in mouse cancer models. One genetic modification in human EPSCs is to target BCL11B and other genes for producing large quantities of human killer cells for cancer immunotherapy. Human and animals EPSCs will be used for investigating genetic factors in human immune cell development and in disease, and for improving animal health including developing treatment for infectious disease.

3. Humanisation of animal genomes for cell and organ transplantation. Large animals such as pig and sheep are useful for studying molecular and cellular mechanisms of human disease. They can serve as potential donors for cell-based therapies and for xeno-transplantation. EPSCs of large animals, for instance, porcine EPSCs, are amenable for efficient genome-editing, which makes it possible to produce donor cells/organs that can evade human immune system attacks and substantially reduce immune rejection of transplanted cells. Extensive genome-editing, including knock-outs and knock-ins in EPSCs will be performed at loci related to immune cell development and function. Generation and use of genetically modified animals from EPSCs will be in collaboration with external experts. Research areas include stem cell biology, single cell genomics, genome-editing, immunology, and biology of specific cell types, tissues and organs.

Professor Pengtao Liu obtained his PhD in Genetics and Development from Baylor College of Medicine in Houston, Texas, USA. He did postdoc training at National Cancer Institute, NIH (USA). Prof. Liu was a faculty member from 2013-2017 at the Wellcome Trust Sanger Institute in Cambridge UK and an affiliated faculty member of Wellcome-MRC Stem Cell Institute of University of Cambridge. Prof. Liu recently moved his lab to the University of Hong Kong. Prof. Liu’s research interests span both fundamental and translational studies in genetics, single cell genomics, development, stem cell, immunity, cancer and interdisciplinary areas. Prof. Liu has research collaborations in U. K., Europe, US and China. Various research projects are available in the lab for postgraduate students.

Faculty information, funding opportunities and application deadlines: