Chen, Li-Yun ORCID: https://orcid.org/0000-0003-1224-6262 (2019) Exploring the effects of gestational diabetes on placental membrane derived stem cells. Doctoral thesis, Keele University.

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Abstract

The progression of regenerative medicine and advanced cell banking technology provide the hope of using perinatal tissue-derived autologous MSCs for personalised medicine. Mesenchymal stem cells (MSCs) derived from placenta, with the advantages of being non-invasive and having fewer ethical issues, are a promising source for cell therapy. The hyperglycaemic intrauterine environment in pregnancies affected by gestational diabetes mellitus (GDM) alters the development of the placenta and may have impacts on placental MSCs behaviours and functions. Therefore, we aimed to investigate the influence of the GDM on placental MSCs and further explore their therapeutic potential.
Placental MSCs were isolated from amniotic membrane (AMSCs) and chorionic membrane (CMSCs). The biological, functional, and immunological characteristics of healthy- and GDM- AMSCs/CMSCs were examined. Compared with healthy MSCs, the GDM-MSCs displayed some levels of alteration in adipogenic capacities and macrophage immunoregulatory properties while comparable immunophenotypes, osteogenesis, chondrogenesis, and T-cell regulation ability were observed in GDM-MSCs.
As the major adverse consequence of GDM is an increased risk of developing diabetes, these women may benefit from cell therapy for diabetes in the future. We developed a step-wise differentiation approach to generating functional insulin-producing cells through a short-term glucose priming period combined with a 16-day serial stimulation of compounds and growth factors, such as activin A, retinoic acid, EGF, GLP1 across different differentiation stages. This approach successfully generated insulin-producing cells from GDM- and healthy- CMSCs which displayed pancreatic beta-cell properties and functions.
Moreover, with more promising potential of CMSCs in regenerative medicine, DNA microarray was performed to examine their transcriptional profiles. Comprehensive investigation of gene expression by microarray and validation of differences between healthy- and GDM- CMSCs via real-time PCR and functional assays revealed enhanced capacities of GDM-CMSCs in wound healing and cardiogenesis compared to healthy-CMSCs. However, significantly reduced expression in detoxification enzymes belonging to the aldehyde dehydrogenase gene families (ALDH1A1/1A2, ALDH2, ALDH3) accounted for downregulation across several metabolic pathways and oxidative stress dysregulation in GDM-CMSCs.
Taken together, understanding these placental stem cell behaviours provides an insight to developing therapeutic applications of GDM-MSCs and heathy-MSCs for future autologous stem cell therapies.

Item Type: Thesis (Doctoral)
Subjects: R Medicine > RC Internal medicine
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
Contributors: Wu, P (Thesis advisor)
Forsyth, NR (Thesis advisor)
Depositing User: Lisa Bailey
Date Deposited: 12 Sep 2019 08:52
Last Modified: 12 Sep 2019 08:52
URI: http://eprints.keele.ac.uk/id/eprint/6814

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