Substance P improves MSC-mediated RPE regeneration by modulating PDGF-BB.

Stem cells have regenerative potentials that can be used for the treatment of critical and incurable diseases. Age-related macular degeneration (ARMD) and diabetic retinopathy are one of the most severe retinal disorders, which are mostly attributed to impairment of retinal pigmented epithelium (RPE). Thus, restoration of RPE is the main therapeutic approach to prevent the development of ocular diseases, such as ARMD. In this study, we have investigated the role of substance P (SP) on bone marrow mesenchymal stem cell (MSC)-mediated RPE regeneration in vitro. The MSCs were primed with SP followed by the addition of conditioned medium (MSCSP-CM) to RPE. The effects of MSCSP-CM on RPE activity was evaluated by assessing viability, proliferation rate, and migration of RPE. Ex vivo long-term culture led to altered cellular characteristics of MSCs by weakening cell viability, cytokine secretion, and differentiation potential. The conditioned medium of early passage MSC (E-MSCCM) enhanced the RPE viability and migration, whereas the late passage MSC (L-MSCCM) hardly influenced the RPE activity. SP priming, however, facilitated the inductive effects of MSC, and SP effect was more distinct in the late passage than in the early passage. Moreover, it was revealed that SP could exert its effects by modulating PDGF-BB secretion in the MSCs. Taken together, these results suggested that SP could restore the therapeutic effects of MSCs on retinal diseases by elevating their proliferative and paracrine activities through PDGF-PDGFR signaling in ex vivo culture.

Substance P Promotes Liver Sinusoidal Endothelium-Mediated Hepatic Regeneration by NO/HGF Regulation.

Liver sinusoidal endothelial cells (LSECs) are highly specialized and involved in hepatic regeneration by interacting with hepatic stellate cells (HSCs) and hepatocytes in a paracrine manner. However, hepatic injury can impair cellular activity and lead to endothelial dysfunction, eventually inducing the development of critical hepatic disease, including cirrhosis. Because LSECs exert their effects through paracrine factors, maintenance of paracrine potentials and survival activity in LSECs under injury stress is a critical strategy for inhibiting disease progression. This study explored the effect of Substance-P (SP) on cell viability, proliferation, and nitric oxide (NO)/hepatocyte growth factor (HGF) production in LSECs. Under noninjured conditions, SP treatment enhanced cell viability, cell proliferation, and HGF/NO secretion in LSECs. In the presence of tumor necrosis factor (TNF)-α-induced inflammatory stress, SP blocked TNF-α-induced endothelial dysfunction, accompanied by elevated cell viability and NO/HGF secretion. Interestingly, SP-primed LSEC-conditioned medium accelerated hepatocyte repopulation without causing morphological alterations. The primitive effect of SP was reversed by endothelial nitric oxide synthase inhibitor or HGF/c-MET inhibitor, indicating the importance of the NO/HGF combination in hepatic regeneration by SP. Taken together, these results suggest SP can protect LSECs from inflammatory stress by NO/HGF, which contributes to hepatocyte repopulation.