Low levels of TGF-β1 enhance human umbilical cord-derived mesenchymal stem cell fibronectin production and extend survival time in a rat model of lipopolysaccharide-induced acute lung injury

Abstract

Abstract. Mesenchymal stem cells (MSCs) are an attractive cellular source for cell-based therapy, tissue engineering and regenerative medicine. However, the use of MSCs is limited by their low incorporation rate in the graft environment. The majority of cells are lost from the graft within 1 month, due to reduced microenvironment or local inflammation at the graft site. The extracellular matrix (ECM) may assist the survival and expansion of MSCs. The present study aimed to identify an effective approach to increase ECM expression levels by MSCs in order to enhance the therapeutic effect and survival rate of MSCs at the injury site. The concentration-dependent effect of transforming growth factor (TGF)-β1 on human umbilical cord (hUC)-MSC proliferation and expression of ECM genes was investigated. MSCs were successfully isolated, cultured and expanded from hUC. A low concentration of TGF-β1 (0.1 ng/ml) exhibited the optimal effect on hUC-MSC proliferation and markedly stimulated the expression of ECM genes, particularly fibronectin (FN). Furthermore, treatment with TGF-β1 caused no alteration in the immunophenotype and differentiation capacity of MSCs. In vivo experiments in rats demonstrated that intravenous injection of control UC-MSCs or TGF-β1-pre-treated UC-MSCs reduced the severity of lipopolysaccharide-induced lung injury, assessed using histology, measurements of the wet-dry lung weight ratio, and neutrophil count and protein concentration in bronchoalveolar lavage fluid. However, the short-term (48 h) therapeutic effects of untreated and TGF-β1-pre-treated UC-MSCs were similar. The survival of MSCs in damaged lungs, determined by Sry gene expression levels, were significantly increased in MSCs pre-treated with TGF-β1. In conclusion, pre-treatment of MSCs with a low concentration of TGF-β1 enhanced the expression of ECM components, particularly FN, thus, improving the survival and potential therapeutic benefits of MSCs. Pre-treatment of MSCs with TGF-β1 may prolong the effective therapy time and represent an efficient therapeutic approach for tissue repair.

Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies

“…UC-MSC primed with TGF-β1 displayed increased proliferation and marked upregulation of extracellular matrix genes, notably fibronectin. TGF-β1-primed MSC survived longer in damaged lungs and reduced the severity of lipopolysaccharide-induced lung injury [ 54 ]. Additionally, some studies have demonstrated that TGF-β1 is capable of inducing the mobilization and migration of BM-MSC to bone remodeling.…”

Intratracheal Transplantation of Amnion-Derived Mesenchymal Stem Cells Ameliorates Hyperoxia-Induced Neonatal Hyperoxic Lung Injury via Aminoacyl-Peptide Hydrolase

“…Nonhuman primate studies demonstrated that 7 days after infusion of allogeneic or autologous MSCs, only a minor fraction of the cells (less than 3%) engraft in different tissues (21); the majority of these cells were found in the kidney, lung, thymus, and skin (22). Recent findings showed that a very low concentration of MSCs was identified in vivo after 4 weeks (23).…”

Stem Cell Based Therapy Option in COVID-19: Is It Really Promising?

“…The other methodologies are using the extracorporeal organ replacement for acute renal failure or fulminant acute liver failure, skeletal stem cell implantation for bone regeneration, which are already under clinical application [33,34]. As the considerable amount of evidence has been obtained from basic research and its translation towards the clinical research, MSCs placed in medical practice as an alternative treatment option as safe and effective cellbased therapies for immune-mediated inflammatory diseases such as graft versus-host disease (GVHD) and systemic lupus erythematosus (SLE) [34][35][36][37].…”

“…One suggested function of stem cells is their ability to regulate the inflammatory response and promote tissue repair and regeneration. MSCs have been demonstrated to improve organ functions in cardiovascular, renal, hepatic, and multiple other disorders [34][35][36][37].…”