Abstract
Fibroblasts are ubiquitous cells that constitute the stroma of virtually all tissues and play vital roles in homeostasis. The poor innate healing capacity of fibroblastic tissues is attributed to the scarcity of fibroblasts as collagen-producing cells. In this study, we have developed a functional ECM mimicking scaffold that is capable to supply spatial allocation of stem cells as well as anchorage and storage of growth factors (GFs) to direct stem cells differentiate towards fibroblasts. Electrospun PCL fibers were embedded in a PEG-fibrinogen (PF) hydrogel, which was infiltrated with connective tissue growth factor (CTGF) to form the 3D nanocomposite PFP-C. The human induced pluripotent stem cells derived mesenchymal stem cells (hiPS-MSCs) with an advance in growth over adult MSCs were applied to validate the fibrogenic capacity of the 3D nanocomposite scaffold. The PFP-C scaffold was found not only biocompatible with the hiPS-MSCs, but also presented intriguingly strong fibroblastic commitments, to an extent comparable to the positive control, tissue culture plastic surfaces (TCP) timely refreshed with 100% CTGF. The novel scaffold presented not only biomimetic ECM nanostructures for homing stem cells, but also sufficient cell-approachable bio-signaling cues, which may synergistically facilitate the control of stem cell fates for regenerative therapies.
Highlights
Fibroblasts are ubiquitous cells that constitute the stroma of virtually all tissues and play vital roles in homeostasis
Electrospun PCL fibers were embedded in a poly(ethylene glycol) (PEG)-fibrinogen (PF) hydrogel, which was infiltrated with connective tissue growth factor (CTGF) to form the 3D nanocomposite PFP-C
The hypothesis was first proven by a comprehensive study of Lee et al[8], where connective tissue growth factor (CTGF; known as CCN2), a 36–38 kDa, cysteine-rich protein of the CCN family[9] was identified to sufficiently promote mesenchymal stem cells (MSCs) to differentiate into fibroblasts
Summary
The CTGF contained scaffold (PFP-C) further significntly lowered the LDH release, in comparison to the CTGF supplemented 2D TCP cultured cells (named TCPc), demonstrating a superior environment for hiPS-MSCs growth. To investigate whether the resulting PFP and PFP-C scaffolds support cellular growth of hiPS-MSCs, the mitochondrial activity CCK-8 assay was used to monitor the relative number of viable cells after one week culture (Fig. 3B). The different proliferation rates and different effects of CTGF arise from both the 3D architecture and the chemistry nature of the PFP nanocomposites: when the same amounts of the cells were seeded on both TCP groups and PFP groups, cell density on TCP groups was lower than that on PFP groups, which might contribute to the lower proliferation rate on PFP groups; the distinct chemistry nature of PFP, compared to tissue culture polystyrene (TCP), provided active interaction with CTGF and overall distinct extracellular environment for the hiPS-MSCs to migrate, proliferate and differentiate Both LDH and CCK data suggest the hiPS-MSCs remained viable and were able to proliferate normally on both the PFP and PFP-C scaffolds. It was noteworthy that the nucleus of the cells exposed to CTGF (TCPc) became significantly larger than the cells without CTGF treatment (TCP) (Fig. S2, Fig. 6B)
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