Characterisation of a pre-osteoblast subset of human mesenchymal stem cells: implications for novel osteoarthritis and osteoporosis treatment development

Project description

Osteoarthritis (OA) and osteoporosis (OP) are the most common age-related skeletal diseases. They seriously affect patient’s quality of life and represent a significant healthcare burden to the UK society. In OP, bone tissue becomes weaker and fractures occur more often as a result of an imbalance between new bone formation and old bone resorption. In OA, sporadic bone resorption episodes occur due to biomechanical stress in response joint loading. New bone formation can become excessive and lead to the destruction of the articular cartilage lining the joint surface. Current treatments for OP target bone resorption, but not the bone formation pathway, whereas for OA there is no disease-modifying therapies and joint replacement remains the ultimate option to alleviate pain.

Our group has a long-standing interest in mesenchymal stem cells (MSCs), which are the earliest progenitors in the bone formation pathway. We have described their native phenotype (CD45-CD271+) and gene expression signature in human bone marrow confirming their undifferentiated and multipotential nature [1,2]. Our recent data has shown that a distinct subset of these cells (CD56+) displays a gene expression signature consistent with pre-osteoblasts (i.e. progenitor cells pre-committed towards bone formation). We therefore hypothesise that this specific subset is numerically and/or functionally impaired in OP and conversely, expanded in OA.

In this project we plan to isolate and characterise the CD271+CD56+ subset of MSCs in OP, OA and control age-matched healthy bone using well-established methodologies of clinical samples processing by tissue digestion, functional assays of stem cell differentiation, immunohistochemistry, multiparameter flow cytometry and confocal microscopy imaging. This will be linked to microCT evaluation of the same tissues for structural correlations. RNA sequencing analysis will be performed to investigate pathway differences between bone forming in OA and bone loss in OP. Sorted cell populations will be treated with candidate bone anabolic or inhibitor molecules for their suitability as novel pathway modifiers.

References

Large-scale extraction and characterisation of CD271+ multipotential stromal cells (MSCs) from trabecular bone in health and osteoarthritis. Jones E, English A, Churchman SM, Kouroupis, Boxall SA, Kinsey S, Giannoudis PG, Emery P, McGonagle D. Arthritis and Rheumatism. 2010, 62:1944-54.

Transcriptional profile of native CD271+ multipotential stromal cells: evidence for multiple fates, with prominent osteogenic and Wnt pathway signaling activity. Churchman SM, Ponchel F, Boxall SA, Cuthbert R, Kouroupis D, Roshdy T, Giannoudis PV, Emery P, McGonagle D, Jones EA. Arthritis Rheum. 2012; 64(8):2632-43.

Entry requirements

This project is available immediately to both Home/EU rate applicants and International applicants who are able to self-fund their studies.

You should hold a first degree equivalent to at least a UK upper second class honours degree in a relevant subject. The ideal candidate will have a background in cell and molecular biology.

Candidates whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study, the Faculty minimum requirements are:

• British Council IELTS - score of 6.5 overall, with no element less than 6.0
• TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23.

How to apply

To apply for this position potential applicants should initially contact the lead supervisor, Dr Elena Jones directly.

Following this, please submit a formal application by completing a Faculty Application form and send this alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates to the Faculty Graduate School.

We also require 2 academic references to support your application. Please ask your referees to send these references on your behalf, directly by email.

 

If you have already applied for other positions, or any scholarships, using the Faculty Scholarship Application form you do not need to complete this form again. Instead, you should email to inform us you would like to be considered for this scholarship project.