Personal profile

Overview

Our research focusses on how human embryo develop and use of human embryonic stem cells (hESc) and induced pluripotent stem cells to understnd human development, for use in clinical cell-based therpy and for modeling human gnetic diseases.  Human pluripotent stem cells (PSCs) can grow indefinitely in a dish while still retaining the ability to produce all the specialised cells in the body and hold great promise for cell therapy disease modeling and biopharma. 1) Work in our (HFEA-licenced) North West Embryonic Stem Cell Centre, in special clean culture rooms, concentrated on generating new hESc lines suitable for treating patients. We use these for a number of projects on human cell differention 2) Based on our novel highly efficient protocol to generate early stage chondrocytes from PSCs, we are working towards a new therapy for cartilage disease (e.g.osteoarthritis) employing PSC-derived chondrocytes and utilising our (HTA and MHRA licenced) clean rooms.  3) We investigate molecules in hPSCs which give them their special characteristics.  3) We are investigating the role of soluble and extracellular matrix derived secreted proteins in hPSCs. We have shown that particular extracellular matrix components and the cellular proteins they bind, are important in regulating stem cell properties and behaviour. 4) We have developed in vitro models for genetic diseases of the skeleton, the vasculature and the kidney. 5) We study regulation of the first few days of human embryo development and we also use the mouse as a model e.g. for placenta development.

Biography

Education

BA University of Cambridge
MA University of Cambridge
PhD University of Cambridge

Employment

AFRC Institute Babraham, Research Station: Postdoctoral Research assistant
MRC Experimental Embryology and Teratology Laboratory: Staff Scientist
University of Copenhagen: Senior Research Associate
University of Manchester: Lecturer/ Senior Lecturer/Reader/Professor

SJK is currently Professor of Stem Cells and Development in the Faculty of Life Sciences University of Manchester. Her first degree and PhD were obtained at the University of Cambridge UK where she became interested in specification of early cell fate decisions in the mammalian embryo. She has worked in London, Copenhagen and for the last >20 years in Manchester.

I have 30 years experience as a developmental biologist working on aspects of early mammalian development. I am also an established international expert on mammalian implantation with a research programme in this area since 1986 leading to over 40 papers. In the last 20 years, thirty of her > 100 papers address issues of establishment of the blastocyst and the inner cell mass (ICM) the source of embryonic stem cells as well as the first differentiation of the embryonic stem cell population to trophectoderm or later the primary embryonic precursor cells (germ layers) in both murine and human embryos. I am co-director of the North West Embryonic Stem Cell Centre (established 2006) jointly hosted by the Univeristy of Manchester (UoM), and Central Manchester NHS Trust (CMMCUHT)(http://www.nwescc.manchester.ac.uk/)..  The remit of the Centre (funded by NWDA and MRC) has been to establish human embryonic stem (hES) cell lines under clean room conditions suitable for therapeutic use and we have generated 17 lines, 7 of these at clinical grade. These lines are now banked in the UK Stem Cell Bank and being used by ourselves and a number of other labs to generate human differentiated cell types.

 

 I have supervised 39 postgraduate research students with 100% degree success and a series of postdoctoral researchers and fellows. I am part of the International Stem Cell Initiative and a past member of the MRC Stem Cell Liaison committee and RCOG/WellBeing Research Advisory Grant committee, Federal Ministry of Education and Research (Germany)  Grant committee, Stem Cells for Safer Medicine Advisory Board; European Tissue Engineering and Regenerative Medicine advisory panel; Royal Society of Medicine Academic Exchange grant committee and NC3Rs UK studentship grant funding committee and a current member of MRC Regenerative Medicine Grant  panel.

I direct the Univeristy of Manchester Clean Rooms for generation of cGMP grade cell products and   University DI for Human Tissue Authority licence for clinical application of human cells as well as Licence Holder for theHFEA licences R0026 for reseach on human embryos and R0171 for derivation of human embryonic stem cell lines. She was founding Chair of the Manchester Tissue Regeneration and Stem Cell Network (now merged into Manchester Regenerative Medicine Network [MaRM] for which she is a Board member) and co-Chair and founder of Mercia Stem Cell Alliance (http://www.msca.ls.manchester.ac.uk/) for promotion of excellence in stem cell science and translation across the north and midlands.

Research interests

 

1) Human embryonic stem cells and induced pluripotent stem cells and the stem cell niche

Within the NW Science fund/MRC funded NW Embryonic Stem Cell Centre (co-Directed by Prof Daniel Brison), the lab has generated 17 human embryonic stem cell (hESC) lines, of which seven are at clinical grade and were derived and banked under an HFEA licence, and are covered by an HTA licence for clinical use. The lines are available to UK and European researchers for differentiation to numerous lineages, for both basic research and also translational studies towards clinical therapies. More recently, my laboratory have been routinely generating human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts and blood cells.  We are interested in basic mechanisms regulating human pluripotent stem cells (PSCs) and have been particularly interested in the extracellular matrix, investigating the nature of the ECM laid down by hESCs and feeder cells on which they are grown.  We have shown that integrin signalling through focal adhesion kinase enhances the pluripotent state of hESCs. We are also investigating the proteins and metabolites in the PSC secretome from pristine carefully controlled hPSCs (iPSCS and hESCs) compared to those progressing to differentiation. This allows us to understand cell signalling pathways indicative of pluripotency versus its loss, as well, as detecting new PSC markers.

2) Use of hPSCs for cell therapy and disease modelling

We have programmes studying targeted differentiation particularly to mesodermal lineages, and most successfully to cartilage (with Prof Tim Hardingham). We developed a serum-free defined protocol to differentiate chondrogenic cells from hESCs and induced pluripotent stem cells (reprogrammed from Blood or fibroblasts) in 14 days. These cells were shown to be able to repair osteochondral defects in an immunocompromised rat model.  We are currently conducting preclinical translation for a new stem cell based therapy for cartilage defects in osteoarthritis or cartilage injury as well as researching the signaling and epigenetic pathways involved in generating chondrocytes form PSCs.  Differential effects of TGF-Beta family growth factors in relation to the ECM (presentation, attachment polarisation) and histone deacetylases form an important focus

 My lab have generated over 20 induced pluripotent stem cell  (iPSc)  lines from patient tissue and unaffected individuals, as well as  protocols to direct  pluripotent stem cell differentiation to a number of tissues (skeletal, nephric, vascular and neural) and are using these for identification of new drug targets.

Skeletal: Specifically we are studying chondrocyte biology in iPSCs generated from patients with pseudochondroplasias and mutations in cartilage oligomeric protein and matrilin 3 mutations (MED), revealing defects in extracellular matrix synthesis and endoplasmic reticulum stress responses. This is throwing light on the pathobiology of these genetic diseases.

Vascular: Having generated iPSCs from patients with a genetic form of stroke called CADSIL, the lab generated smooth muscle and endothelial cells in collaboration with Dr Tao Wang. We then co-cultured these two cell types to model the vascular disease phenotype showing significantly compromised signalling between the two cell types. My group is using Crispr/Cas9 gene editing to create mutations in wild-type SCs, mimicking developmental genetic diseases in endothelial, kidney and cartilage research.

Kidney: We have reproducibly generated kidney progenitors and kidney organoids from 4 different PSC lines and are using these protocols to understand genetic diseases affecting the kidney (collaboration with Prof Adrian Woolf). We have started to generate the first insertional mutations in the HNF-1 Beta gene of PSCs using gene editing. The research team are currently testing whether transplantation of these precursor cells ameliorate chronic kidney disease in a murine model and examining the effect of micro RNAs and other agents on the differentiation of different nephric lineages..

3) Early human embryonic cell fate

We are characterizing the molecular progress on preimplantation human development and fate of inner cell matrix (ICM) cells, in terms of survival versus death and early differentiation. Representative amplification of mRNAs from single cells and embryos allows us to map gene expression patterns during development of individual human embryos and in single blastomeres. Using bioinformatic approaches with single embryos and single cell transcript array data we have identified new stage specific pathways and genes in the early embryo in collaboration with Prof Daniel Brison. This has revealed novel epigenetic and metabolic changes correlating with stage and tissue.  We are also comparing the transcriptome of the ICM and trophectoderm of the embryo to that of hESCs giving critical insight into their similarities and differences

4) Implantation

In the cascade of interactions involved during implantation, we discovered a novel steroid regulated mechanism for initial attachment of embryos depending on binding of blastocyst receptors to carbohydrates on uterine luminal epithelial glycoproteins.  We also demonstrated cellular and molecular aspects of the role of Leukemia inhibitory factor in implantation in mice. In collaboration with the West wood and Aplin groups we continue to investigate the mechanism of mammalian embryo attachment to the uterus and implantation.

 

Teaching

Stem Cell Biology, Developmental Cell Biology, Reproductive Biology

Expertise related to UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being
  • SDG 14 - Life Below Water

External positions

MRC Regenerative Medicine Board

20162019

Research Beacons, Institutes and Platforms

  • Manchester Regenerative Medicine Network
  • Advanced Materials in Medicine
  • Digital Futures
  • Christabel Pankhurst Institute

Keywords

  • stem cells
  • iPSCs
  • Disease modelling
  • stem cell therapy

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