Beating mesenchymal stem cell senescence with materials that organise growth factors.

点击翻译按钮获取中文摘要

Mesenchymal stem cells (MSCs) from the adult bone marrow can differentiate into cells that support the regeneration of tissues such as bone cartilage, ligament and tendon. They also have immunomodulatory properties and so are becoming more widely used as 'drugs' in transplant procedures to help prevent rejection e.g. in islet transplants and in graft vs host disease. Further, they can support the growth of the blood-forming stem cells of the bone marrow and can have regenerative roles in helping in blood diseases such as leukaemias. Therefore, they have the potential to provide a key role in strategies to underpin a wide range of next-generation disease therapies.MSCs are isolated from the bone marrow in low numbers (1000s) and yet a cell therapy would require tens of millions of MSCs per dose and forming a company to supply the therapies would require the ability to produce billions of cells in order to meet the demand of healthcare suppliers at a cost that can be justified.As MSCs grow in culture, out of the regulation of the bone marrow, they change phenotype (differentiate) and age (leading to the stopping of growth - senescence). To provide MSC therapies, both of these hurdles need to be overcome.We have developed polymers that can control the presentation of extracellular matrix (ECM) proteins that MSCs interact with in the bone marrow in ways that allow for better MSC growth. ECM proteins contain cryptic peptide sequences that, when exposed, allow cell adhesion to them and allow signalling proteins, such as growth factors, to bind to them allowing better control of cell signalling.In this project, we will study primary human MSC growth in relation to the biological presentation of the ECM proteins with growth factors in order to optimise MSC growth in vitro. We will use both biological (PCR, flow cytometry, qPCR, microscopy) and biomechanical (mechanical cytometry, nanoindentation and Brillouin microscopy) to look for markers of preserved MSC phenotype and senescence (eg stiffening of the cell nucleus). We will also employ transcriptomics (RNAseq) and metabolomics to look for signalling targets that we can inhibit as drug targets to further prevent MSC ageing while promoting MSC expansion.The project is in collaboration with the industrial partner QKine who develop animal-product free growth factors for stem cells.