Abstract
Mesenchymal stromal cells (MSC) secrete factors that contribute to organ homeostasis and repair in a tissue specific manner. For instance, kidney perivascular mesenchymal stromal cells (kPSCs) can facilitate renal epithelial repair through secretion of hepatocyte growth factor (HGF) while the secretome of bone marrow MSCs gives rise to immunosuppression. Stromal cells function in a complex 3-dimensional (3D) connective tissue architecture that induces conformational adaptation. Here we tested the hypothesis that surface topography and associated cell adaptations dictate stromal cell function through tuning of the cytokines released. To this end, we cultured human bone marrow and kidney perivascular stromal cells in the TopoWell plate, a custom-fabricated multi-well plate containing 76 unique bioactive surface topographies. Using fluorescent imaging, we observed profound changes in cell shape, accompanied by major quantitative changes in the secretory capacity of the MSCs. The cytokine secretion profile was closely related to cell morphology and was stromal cell type specific. Our data demonstrate that stromal cell function is determined by microenvironment structure and can be manipulated in an engineered setting. Our data also have implications for the clinical manufacturing of mesenchymal stromal cell therapy, where surface topography during bioreactor expansion should be taken into account to preserve therapeutic properties.
Highlights
Mesenchymal stromal cells are immunomodulatory and regenerative cells originally isolated from the bone marrow
For example, that kidney derived perivascular stromal cells display a distinct organotypic gene expression profile as well as different functionality compared to bmMSCs9. kPSCs were, in contrast to bmMSCs, able to support kidney epithelial wound healing, which could be attributed to the specific production of hepatocyte growth factor (HGF) by kPSCs9
Treatment of bmMSCs with the small molecule dibutyryl-cAMP induced the expression of a panel of pro-osteogenic cytokines among which BMP2 and IGF1 resulting in a profound increase in in vivo bone formation[20,21]
Summary
Mesenchymal stromal cells are immunomodulatory and regenerative cells originally isolated from the bone marrow (bmMSCs). For the immunomodulatory potential of MSCs, for example, indoleamine 2,3-dioxygenase (IDO), prostaglandin E2, macrophage colony-stimulating factor (M-CSF) and interleukin (IL)-6 are of major importance[1,2], while for vascular stabilization the secretion of VEGF and angiopoietin-1 is essential[3,4] Due to these characteristics, bmMSCs are an interesting cell source for cellular therapy for, amongst others, graft versus host disease (GvHD) and kidney transplantation and currently several trials are being performed with these cells[2,5,6]. We were able to optimize clonogenic growth of IPSCs, growth of human hepatocytes and bmMSC proliferation where we observed a correlation between cell shape and cell physiology, based on high content imaging of single biomarkers[12,13,14] This system does, not allow the assessment of the secretome of the cells studied. To allow analysis of multiple genes or secreted proteins we subsequently developed the TopoWellPlate (TWP), comprising a 96 well plate with unique topographies selected based on cell shape diversity from the earlier TopoChip experiments[15]
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