Differentiation of human ES cells to haematopoietic lineages
Project Leader(s): Dr Majlinda Lako (in collaboration with Dr Miodrag Stojkovic, Dr Lesley Forrester and Dr Lyle Armstrong)
Transplantation of haematopoietic stem cells (HSC) as a treatment regime for leukaemia requires the availability of high quality sources of tissue matched bone marrow or umbilical cord blood. Suitable bone marrow is often in short supply and cord blood, although bankable, contains much lower numbers of HSCs which makes it less suitable for transplantation into adults. The directed differentiation of human embryonic stem (ES) cells towards HSCs offers a potentially attractive alternative to these conventional sources since the parent ES cells may be expanded indefinitely in culture and thus there should be no limit to the numbers of HSCs obtainable. Another advantage of ES derived HSC is that in theory at least, they represent a more ‘youthful ‘ population of cells than those obtainable from adult bone marrow which has been subject to environmental insults and could be expected to have accumulated DNA damage such a shortened telomeres or oxidative lesions. More importantly transplantation of ES cell - derived HSCs and their suggested ability to induce haematopoietic chimerism may pave the way for transplants with other ES cell – derived tissues without the need for continuous immunosuppression Human embryonic stem (ES) cells are pluripotent cell lines that are derived from the inner cell mass of human blastocysts and are characterised by their unique ability to grow indefinitely in culture while maintaining their pluripotency and normal karyotype. They can be differentiated into potentially, any mature cell type and genetically manipulated to achieve introduction or deletion of specific genes, resulting in the development of therapeutic attributes which will be transferred to any cell type produced subsequently by differentiation. Human ES cells were first derived and successfully propagated in 1998. The last six years have witnessed an exponential increase in experiments aimed at improving culture conditions, genetic manipulation and differentiation regimes to produce human cells for transplantation and drug testing. However the challenge remains to produce mature, functional and pure derivatives of cells types that can be utilized for transplantation purposes. Our Stem Cell Group has been succesful in deriving a new human embryonic stem cell line
We are now focusing on targeted differentiation of these cells towards the haematopoietic lineage using a variety of approaches.
Haematopoietic differentiation of human ES cells (hES1-NCL). A – 14 days culture of human hES-NCL1; B - CFU-GEMM colony from differentiated human hES-NCL1; C – BFU-E colony from differentiated human hES-NCL1; D – CFU-GM colony from differentiated human hES-NCL1.
References:
Lako, M., Armstrong, L., Cairns, P.M., Harris, S., Hole, N. and Jahoda, C. (2002) Hair follicle dermal cells repopulate the mouse haematopoietic system. Journal of Cell Science 115:3967-3974.
Lako, M., Lindsay, S., Lincoln, J., Cairns, P.M., Armstrong, L. and Hole, N. (2001) Characterisation of Wnt gene expression during the differentiation of murine embryonic stem cells in vitro: role of Wnt3 in enhancing hematopoietic differentiation. Mechanisms of Development 103:49-59.
Staff Profiles
- Dr Louise Hyslop
Telephone: 0191 219 4740
Email: l.a.hyslop@ncl.ac.uk - Dr Majlinda Lako
Telephone: 0191 241 8688
Email: majlinda.lako@ncl.ac.uk
