How does growth restriction in the womb programme fat stem cells in pig and human?

Supervisors: Xavier Donadeu, Paul Fowler, Amanda Drake, Cristina Esteves

Project description:

Intrauterine growth restriction (IUGR) is a significant public health burden, with as many as 40% new-borns affected in some developing countries, and is a leading cause of low birth-weight and neonatal mortality worldwide1. IUGR has severe consequences for post-natal development, characterized by increased body fat formation at the expense of essential tissues such as muscle2. This abnormal pattern of tissue development significantly increases the risk of important diseases during adult life including hypertension, diabetes, psychiatric disorders and impaired musculoskeletal strength.

The pig is increasingly becoming a model of choice to investigate the consequences of IUGR in different body tissues2. Clear advantages over other model species are that pigs naturally produce litters with at least one littermate that has a phenotype very similar to that of humans affected by IUGR. Importantly, IUGR piglets can be studied in relation to normal littermates thus avoiding confounding effects of litter/genetic background. In addition, the pig provides the model of choice for cardiovascular and metabolic disease, two key clinical features of IUGR.

Results from in vitro studies in our (unpublished) and other laboratories3-5 suggest that programming of progenitor cell populations towards an adipogenic fate at the expense of other mesenchymal lineages (endothelia, muscle, bone) occurs in utero, underpinning dysregulated post-natal tissue development in IUGR individuals. Recent ground-breaking studies in humans identified a subset of perivascular cells with immunophenotype, CD146+/CD31-/CD45-, as genuine native adipogenic precursors across body tissues6. Crucially, we have developed the technology to isolate these cells from tissues of large animal species7 including pig.

Using this knowledge, this project will investigate the molecular basis of mesenchymal cell programming by IUGR by taking a comparative approach using pig and human tissues. This will provide the basis for developing effective interventional strategies using the pig as a preclinical model in later studies. The objectives will be:

(1) To establish the effects of IUGR on adipogenic progenitor populations by determining genome-wide gene expression signatures in cells from different foetal tissues (subcutaneous, skeletal muscle, placenta) of IUGR and normal littermates

(2) To compare gene expression patterns and in vitro phenotypes between porcine and human cells

The student will acquire a solid understanding of stem cell/developmental biology and the mechanisms of foetal programming. He/she will become proficient in a wide variety of cell/molecular biology techniques including fluorescence-activated cell sorting, culture and differentiation of stem cells, immunochemistry, immunoblotting, next-generation sequencing and qPCR. The project brings together the complementary expertise of the co-supervisors in Foetal programming (Prof. Fowler and Dr. Drake) and Stem Cell Biology (Dr. Donadeu and Dr. Esteves) in a collaboration that will benefit from state-of-the art research facilities at the host institutions of Edinburgh and Aberdeen.

References:

[1] Lee et al. 2013 The Lancet Global Health 1:e26

[2] Gonzalez-Bulnes et al. 2016 Theriogenology 86:110

[3] Sukarieh et al. 2014 Human reproduction 29:2287

[4] Pillai et al. 2016 PLOS ONE 11:e0168382

[5] Oreffo et al. 2003 Bone 33:100

[6] Crisan, Yap & Casteilla 2008 Cell Stem Cell. 3:301

[7] Esteves et al. 2017 Stem Cell Research & Therapy 8:80

Other: