While the studies on the material interaction with mesenchymal stem cells (MSCs) have been mainly focused on the ability of materials to provide environment to regulate cell viability, proliferation or differentiation, the therapeutic effects of MSC-material constructs may result from the secretion of immunomodulatory and angiogenic cytokines from MSCs. Here, electrospun scaffolds composed of fibers in random, aligned and mesh-like patterns were fabricated, and the paracrine behavior of adipose-derived MSCs (Ad-MSCs) on the scaffolds were investigated in comparison to the cell culture via conventional microplates. It was found that the Ad-MSCs on the electrospun fibers produced significantly higher levels of anti-inflammatory and pro-angiogenic cytokines compared to those cultured on microplates. The enhanced modulatory effects of the secreted products of Ad-MSCs on fibrous electrospun scaffolds were also proven in the cultures of endothelial cells and the LPS-stimulated macrophages, with three types of scaffolds showing distinct influences on the paracrine function of Ad-MSCs. In a skin excisional wound-healing model in rat, the conditioned medium collected from the MSC-scaffold system accelerated the wound closure, promoted the macrophage recruitment and enhanced the polarization of macrophages toward the pro-healing phenotype in the wound bed. Our study demonstrates that the fibrous topography of scaffolds is a key material property that modulates the paracrine function of cells. The discovery elucidates a new aspect of material functions, laying the foundation for developing scaffold materials to promote tissue regeneration/repair through guiding the paracrine signaling network.

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Diabetic nephropathy (DN) is one of the most important diabetic microangiopathies. The epithelial-to-mesenchymal transition (EMT) plays an important role in DN. The physiological role of microRNA-21 (miR-21) was closely linked to EMT. However, it remained elusive whether tongxinluo (TXL) ameliorated renal structure and function by regulating miR-21-induced EMT in DN. This study aimed to determine the effect of TXL on miR-21-induced renal tubular EMT and to explore the relationship between miR-21 and TGF-β1/smads signals. Real-time RT-PCR, cell transfection, in situ hybridization (ISH), and laser confocal microscopy were used, respectively. Here, we revealed that TXL dose dependently lowered miR-21 expression in tissue, serum, and cells. Overexpression of miR-21 can enhance α-smooth muscle actin (SMA) expression and decrease E-cadherin expression by upregulating smad3/p-smad3 expression and downregulating smad7 expression. Interestingly, TXL also increased E-cadherin expression and decreased α-SMA expression by regulating miR-21 expression. More importantly, TXL decreased collagen IV, fibronectin, glomerular basement membrane, glomerular area, and the albumin/creatinine ratio, whereas it increased the creatinine clearance ratio. The results demonstrated that TXL ameliorated renal structure and function by regulating miR-21-induced EMT, which was one of the mechanisms to protect against DN, and that miR-21 may be one of the therapeutic targets for TXL in DN.