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Interrogating the cellular and molecular mechanisms of tissue fibrosis

Primary supervisor: Dr Jill Johnson, Aston University

Non-academic partner: Jan Hendrikx, Stemcell Technologies

Project Title: Interrogating the cellular and molecular mechanisms of tissue fibrosis

Project description:

Background: Scar formation is a vital mechanism of tissue repair following injury. However, healthy tissue repair can develop into pathological fibrosis, which ultimately leads to tissue destruction and organ failure. Fibrosis is associated with chronic inflammation, oxidative stress, and ageing. However, there are currently no treatment options for organ fibrosis, and these diseases impose a significant burden on public health care systems and have detrimental impacts on patient quality of life. Importantly, little is known about the factors that initiate fibrosis. This studentship will build on previous work in Dr Jill Johnson’s research group that has identified pericytes as the primary driver of fibrosis. Pericytes are a type of mesenchymal progenitor cell that support capillaries throughout the body1 and are particularly important in maintaining healthy tissue structure. Importantly, pericytes are strongly associated with tissue fibrosis in the lung, liver, and kidney.2-4 Recent studies have shown that pericytes contribute to fibrosis by uncoupling from local blood vessels, followed by migration to the site of inflammation and differentiation into scar-forming myofibroblasts5,6 (Figure 1). However, the mechanism by which chronic inflammation affects the differentiation capacity of pericytes is currently unknown.

Mesenchymal stem cells (MSCs) are multipotent adult stem cells with self-renewal and differentiation capacity that can be readily isolated from bone marrow, but all tissues harbor MSC-like cells as part of the microvasculature, i.e. pericytes. MSCs can differentiate into multiple cell lineages under specific differentiation conditions. Intriguingly, recent studies have shown that inflammatory mediators affect the differentiation capacity of MSCs, i.e. low levels of TNF-α promote osteogenic differentiation in bone marrow-derived MSCs.7

 

Aims: To investigate the mechanisms regulating the differentiation capacity of pericytes in health and disease.

Hypothesis: Pro-fibrotic growth factors will lead to pericyte-myofibroblast transition and contribute to fibrosis.

Objectives:

  1. Using in vitro two-dimensional pericyte culture, we will investigate the mechanisms of pericyte-to-myofibroblast differentiation.
  2. Differentiation assays will be performed on healthy and inflammatory-mediator treated human pericytes. Readouts will include qPCR array analysis (Human Mesenchymal Stem Cell qPCR Array, Stemcell Technologies) and MSC differentiation assays to assess the capacity of pericytes to differentiate into adipocytes, chondrocytes, and osteocytes using MesenCult™ differentiation kits (Stemcell Technologies).
  3. Experiments will be performed to validate the findings from the first two aims in an in vivo setting.

 

Expected outcomes. Pericytes will respond to inflammatory mediators by transforming into myofibroblasts and demonstrating more robust differentiation capacity.

REFERENCES: 1. Fuxe J et al. (2011) Am J Pathol 178:2897 2. Johnson JR et al. (2015) Am J Physiol Lung Cell Mol Physiol 308(7):L658 3. Mederacke I et al. (2013) Nat Commun 4:2823 4. Wu CF et al. (2013) Am J Pathol 182:118 5. Bignold R et al. (2021) Front Allergy 2:786034.6. Bignold R et al. (2022) Respir Res. 2022 23(1):183. 7. Russell T et al. (2021) Cells 10(2):341.8. Johnson JR (2004) Am J Respir Crit Care Med 169(3):378-85.

 

Candidates are encouraged to contact Dr Jill Johnson to discuss the project before applying if they wish to.

Contact: Dr Jill Johnson, Aston University

Application

Deadline: 20 January 2023

To apply for a CASE studentship, please check your eligibility and complete the MIBTP application process.

Please ensure that you;

  • Apply directly to Aston Univeristy
  • Clearly state you are applying for a CASE project and stipulate the proejct title.