Human fetal mesenchymal stem cell fate after intrauterine transplantation

Lead Research Organisation: Imperial College London
Department Name: Unlisted

Abstract

Stem cells form healthy tissues and help the body repair damaged tissue, and so are being investigated as potential treatments for both inherited and acquired diseases. Currently, the choice for research is between stem cells from embryos, and those from adult tissues. Embryonic stem cells form more tissue types than adult stem cells, but raise ethical concerns and their development is too uncontrolled to allow transplantation in humans. Fetal stem cells are somewhere in between, growing better and into more tissue types than adult ones. We recently identified a new type of fetal stem cell, which circulates in the blood in the first months of fetal life, and develops in the laboratory into muscle, bone, brain and other tissues. A variety of inherited diseases affecting muscle, the skeleton, brain and other tissues cause organ damage in early life. Examples include muscular dystrophy, brittle bone disease and rare enzyme deficiencies. Transplanting fetal stem cells inside the womb should lead to much greater numbers of stem cells before damage occurs, and therefore better tissue repair than if given after birth. Giving them inside the womb before immunity develops should also reduce the chance of stem cells being rejected. Because fetal stem cells can be collected from an affected fetus in early pregnancy, they could be used replace a defective gene, before being put back inside the same fetus. We will test the ability of fetal stem cells given inside the womb to spread and contribute to developing fetal tissues. Because this is not ready to test in humans, it must first be tried in the laboratory in a mouse model. There is no alternative way of assessing whether transplanting stem cells inside the womb actually works. We will also insert a harmless marker gene to test whether fetal stem cells can be safely modified in the laboratory and still grow in sufficient numbers to be useful for treatment. Fetal stem cells can also be collected from elective abortion, and their ability to differentiate into nerve cells suggests an additional role in repairing brain damage at birth. Demonstrating that fetal stem cells contribute to fetal organ development inside the womb is an essential prerequisite before this type of treatment could be tried in humans. If successful, it may open the door to development of a new approach to disabling genetic conditions for which the only therapeutic option currently is termination of pregnancy.

Technical Summary

Adult mesenchymal stem cells (MSC) are under investigation for therapeutic applications in cell transplantation, tissue engineering and repair. We recently isolated a more primitive population of human fetal mesenchymal stem cells (hfMSC) from first trimester fetal blood and liver, which can be expanded in culture, are readily transducible with integrating vectors, and differentiate along multiple mesenchymal and non-mesenchymal lineages. hfMSC may have therapeutic application in utero, either allogeneic, or as autologous donors of therapeutic genes in inherited deficiency diseases. Transplantation in utero should capitalise on the ontological immaturity of developing tissues and fetal immune naivete. This approach has been validated by pilot work showing multi-organ engraftment and site-specific tissue differentiation after hfMSC transplantation in fetal sheep and rodents. In vitro differentiation of hfMSC into neurons and oligodendrocytes further suggests a role in repair of perinatal brain injury. Understanding stem cell fate after intrauterine transplantation is a necessary prerequisite to further development of this approach in experimental models of debilitating human disease. We seek funding for two post doctoral workers with related consumables to determine hfMSC fate in parenchymal organs and bone marrow after intrauterine transplantation in wild type fetal mice. We will establish the optimal delivery route (intravascular, intraperitoneal, intracerebral, intramuscular and intrahepatiic) and cell dose for engraftment of hfMSC after intrauterine transplantation and determine both site-specific differentiation in target organs and microchimerism in bone marrow and other sites of MSC migration. Because ex vivo gene therapy is currently limited by risks of insertional mutagenesis, we will also explore clonal expansion of hfMSC infected with a marker gene at low copy number to allow site-directed insertional analysis of vector integration within safe genomic loci prior to transplantation. This work integrates clinical and basic science groups with expertise in fetal medicine, fetal and neural stem cell biology, gene therapy, intrauterine transplantation, and adult mesenchymal stem cell biology. Moreover, each applicant brings strengths in related areas that will be useful in placing the results in context and developing downstream applications. This proposal is relevant to several of the MRC?s strategic goals, and offers a realistic opportunity of consolidating a UK lead in the development of intrauterine therapy using a novel stem cell source.
 
Description RCUK fellowship Stem Cell Repair (Profs N Fisk & M Parker)
Amount £125,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start  
 
Description SYNTHGENEDELIVERY (Ex vivo gene delivery for stem cells of clinical interest using synthetic processes of cellular and nuclear import and targeted chromosomal integration)
Amount £2,400,000 (GBP)
Funding ID 18716 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 12/2005 
End 05/2009
 
Description Collaboration with Dr Dominique Bonnet 
Organisation Cancer Research UK
Department Cancer Research UK London Research Institute (LRI)
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration with Dr Dominique Bonnet at Cancer Research UK on oncogenicity of fMSC in vivo.
Impact NA
 
Description Collaboration with Prof Yves Bigot 
Organisation National Center for Scientific Research (Centre National de la Recherche Scientifique CNRS)
Department The Institute of Physics and Chemistry of Materials of Strasbourg (IPCMS)
Country France 
Sector Academic/University 
PI Contribution Collaboration with Prof Yves Bigot on non viral integration using transposons. This resulted in a European Union Framework VI grant in 2005: Ex vivo gene delivery for stem cells of clinical interest using synthetic processes of cellular and nuclear import and targeted chromosomal integration. (PI Y Bigot and 4 partners) €2.4 million over 3 years.
Impact NA
 
Description hfMSC transplantation in a murine model of osteogenesis imperfecta 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Media (as a channel to the public)
Results and Impact Related work built on that in the MRC grant, dealing with hfMSC transplantation in a murine model of osteogenesis imperfecta (brittle bone disease) was the subject of a press release after presentation at the International Society of Stem Cell Research Meeting in 2007, which was reported in the New Scientist.
Dr Mehmet undertook a number of radio interviews and podcasts on the general subject of stem cells, and an interview on the BBC News channel.


NA
Year(s) Of Engagement Activity 2007