Adipose Stromal Cell-Secretome Counteracts Profibrotic Signals From IPF Lung Matrices

Abstract

Introduction: Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease characterized by excess deposition and altered structure of extracellular matrix (ECM) in the lungs. The fibrotic ECM is paramount in directing resident cells toward a profibrotic phenotype. Collagens, an important part of the fibrotic ECM, have been shown to be structurally different in IPF. To further understand the disease to develop better treatments, the signals from the ECM that drive fibrosis need to be identified. Adipose tissue-derived stromal cell conditioned medium (ASC-CM) has demonstrated antifibrotic effects in animal studies but has not been tested in human samples yet. In this study, the collagen structural integrity in (fibrotic) lung tissue, its interactions with fibroblasts and effects of ASC-CM treatment hereon were studied.Methods: Native and decellularized lung tissue from patients with IPF and controls were stained for denatured collagen using a collagen hybridizing peptide. Primary lung fibroblasts were seeded into decellularized matrices from IPF and control subjects and cultured for 7 days in the presence or absence of ASC-CM. Reseeded matrices were fixed, stained and analyzed for total tissue deposition and specific protein expression.Results: In both native and decellularized lung tissue, more denatured collagen was observed in IPF tissue compared to control tissue. Upon recellularization with fibroblasts, the presence of denatured collagen was equalized in IPF and control matrices, whereas total ECM was higher in IPF matrices than in the control. Treatment with ASC-CM resulted in less ECM deposition, but did not alter the levels of denatured collagen.Discussion: Our data showed that ASC-CM can inhibit fibrotic ECM-induced profibrotic behavior of fibroblasts. This process was independent of collagen structural integrity. Our findings open up new avenues for ASC-CM to be explored as treatment for IPF.

Decellularized diseased tissues: current state‐of‐the‐art and future directions

“…The application of adipose tissue-derived stromal cell conditioned medium (ASC-CM) in the ex vivo culture model resulted in less ECM deposition. 154 This research suggested that ASC-CM probably inhibit fibrotic ECM-induced profibrosis of fibroblast, and confirmed the efficiency of the ex vivo platform.…”

Species-dependent impact of immunosuppressive squalene-gusperimus nanoparticles and adipose-derived stem cells on isolated human and rat pancreatic islets

“… 10 , 12 These cells also have a high regenerative effect on surrounding tissue due to the capacity to produce soluble trophic factors. 13 This can promote survival, regeneration, and function of different cells including those of pancreatic islets through paracrine mechanisms driven by MSCs-derived growth factors, cytokines, and chemokines. 9 , 14 The factors secreted by MSCs can also modulate the immune system by inhibition of activation and proliferation of lymphocytes T and B, and dendritic cells, as well as by induction of polarization of macrophages from M1 to M2 state.…”

Design and experimental studies on squalene-gusperimus nanoparticles for managing immune responses against microencapsulated islets in the immediate posttransplant period

“…MSCs have also been shown to improve the insulin secretory response of islets and prolong their survival [29]. The beneficial effects of MSCs in pancreatic islets have been attributed to the secretion of different bioactive paracrine molecules such as growth factors, cytokines, and chemokines [125], as well as their capacity to form extracellular matrix (ECM) as structural support and reservoir for bioactive molecules [123]. However, although the use of MSCs is a very promising approach for application in the clinic, so far, have not led to enough evidence that they are effective in treating diseases [29].…”