Tissue origin dictates mesenchymal stromal cell chemokine and chemokine receptor repertoire and predicts in vitro chemotactic activity under homeostatic and inflammatory conditions

Thirlwell, Kayleigh Laura (2018) Tissue origin dictates mesenchymal stromal cell chemokine and chemokine receptor repertoire and predicts in vitro chemotactic activity under homeostatic and inflammatory conditions. PhD thesis, University of Glasgow.

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Abstract

Due to their anti-inflammatory and immunomodulatory properties, mesenchymal stromal cells (MSCs) are under intense investigation in many pre-clinical and clinical trials as a potential cellular therapy to be used in an array of clinical settings. The majority of the literature surrounding MSC phenotype and function is derived from studies focusing on bone marrow (BM) derived MSCs. Recently however, it has become apparent that MSCs can be isolated in a less invasive manner, from the majority of tissues in the human body. In light of this, many studies have been published promoting the use of alternative tissue sources for MSC isolation with no thorough standardised comparison of the phenotype or potential in vivo function of these MSCs. The advanced therapeutics department within the Scottish National Blood Transfusion Service (SNBTS) is involved in the development and optimisation of several cellular therapies including the use of MSCs within various clinical settings. SNBTS has access to fully consented human tissues rich in MSCs including; pancreatic islets, visceral adipose tissue, liposuction aspirate, bone marrow and umbilical cord. Therefore this study aimed to objectively compare the phenotype and potential in vivo function of MSCs isolated from the aforementioned tissues in a stringent, standardised manner in order to assess if MSCs isolated from one specific tissue source might be optimal for use within the clinic. The beneficial therapeutic effect of MSCs often depends on their ability to migrate to target tissues and interact with residing or migratory immune and non-immune cells, frequently within an inflammatory environment. Therefore this study focussed on how MSCs might migrate in vivo by assessing and comparing MSC chemokine receptor expression, whilst also assessing and comparing MSC chemokine secretion profiles to understand which immune cells MSCs might attract, and therefore potentially interact with, in vivo. This study found that chemokine receptor expression by MSCs isolated from islet, visceral adipose, adipose, bone marrow and umbilical cord tissues was very low, with CXCR4, CCR7 and ACKR3 expression being restricted to visceral adipose and bone marrow derived MSCs. Inflammatory chemokines were secreted at very high levels by MSCs isolated from all of the aforementioned tissues, which induced migration of target immune cells towards all MSCs tested in vitro and in vivo, importantly however, the tissue origin of MSCs dictated the quantities of immune cells attracted. This study highlighted that the tissue origin of MSCs could affect MSC in vivo migratory capacity and their ability to chemoattract surrounding immune cells, thereby potentially influencing their clinical performance.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: mesenchymal stromal cells, MSCs, mesenchymal stem cells, chemokine, chemokine receptor.
Subjects: Q Science > QR Microbiology > QR180 Immunology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Supervisor's Name: Graham, Professor Gerard and Campbell, Professor John
Date of Award: 2018
Depositing User: Miss Kayleigh Thirlwell
Unique ID: glathesis:2018-8951
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 11 Apr 2018 10:26
Last Modified: 09 Oct 2018 12:14
URI: http://theses.gla.ac.uk/id/eprint/8951

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