CD317 stabilizes TNFR1 and confers the anti-inflammatory functions of MSCs via NF-κB/TSG6 pathway

Abstract

Background Although both pre-clinical and clinical studies show promising outcomes, resulting in rapid growth of clinical trials of MSC-based therapies in recent years, the heterogeneity and therapeutic inconsistency of MSCs have severely hampered their clinical applications. Purifying homogenous MSC populations with enhanced specific functions represents one promising approach. We have demonstrated recently that the CD317+ MSCs have enhanced anti-inflammatory functions and improved therapeutic efficacy and consistency. Methods In the current study, we performed both in vitro and in vivo investigations to delineate whether and how CD317 regulates the immune modulation function of MSCs. Results Our data here indicate that the CD317 directly contributes to the immune suppression function of MSCs stimulated by TNF-α through up-regulating TSG6 via CD317/lipid-raft/TNFR1 complex. The CD317 stabilizes the TNFR1 complex, resulting in hyper-activation of the NF-κB pathway and up-regulation of TSG6, which confers the therapeutic effects of MSCs on the mouse model of ALI (acute lung injury) and IBD (inflammatory bowel disease). Conclusions Thus, the CD317 stabilizes TNFR1 and confers the anti-inflammatory functions of MSCs via NF-κB/TSG6 Pathway.

1. Introduction

Mesenchymal stem/stromal cells (MSCs) have strong immune modulation and regenerative capabilities, leading to extensive and intensive investigations in treating various types of diseases [1–5]. Although both pre-clinical and clinical studies show promising outcomes, resulting in rapid growth of clinical trials of MSC-based therapies in recent years, the heterogeneity and therapeutic inconsistency of MSCs have severely hampered their clinical applications [1, 2, 4, 6–9]. In addition to other strategies for reducing the heterogeneity and improving the therapeutic efficacy, such as modifications in cell expansion condition and functional target gene over-expression [1, 7, 10–12], purifying homogenous MSC populations with enhanced specific functions represents another promising approach [1, 4, 7–9].

And we have demonstrated recently that the CD317+ MSCs have enhanced anti-inflammatory functions and improved therapeutic efficacy and consistency [13, 14]. CD317+ MSCs have improved differentiation capabilities and enhanced immune suppression activities through expressing higher levels of TSG6 [13], and stabilizing the TSG6 by high level of PTX3 [14]. They showed improved therapeutic effects in the mouse model of ALI (acute lung injury) [13], and improved therapeutic consistency in the mouse model of IBD (inflammatory bowel disease) [14].

CD317, also known as Tetherin or BST2 (Bone Marrow Stromal Cell Antigen 2), is firstly identified as membrane antigen selectively expressed on terminal differentiated human B cells [15, 16] and then on the bone marrow stromal cells [17]. Later functional investigations indicate that the CD317, as an integral membrane protein, might contribute to the homeostasis of endoplasmic reticulum, vesicle coat assembly and cargo sorting [18]. It is localized to the lipid raft, and mediates membrane protein internalization via the clathrin-dependent pathway [19, 20]. In accordance with its function, CD317 has been detected in various types of cells with varying degrees and is highly expressed in a number of specialized cell types [21]. In addition to the most studied function of CD317 as a virus restriction factor suppressing the replication and secretion of virus [22], it also play an important role in regulating multiple functions of cells, such as promoting the adhesion [23], mig