TNFAIP6 defines the MSC subpopulation with enhanced immune suppression activities

Abstract

Background Mesenchymal stromal/stem cells (MSCs) have been intensively investigated in both pre-clinical and clinical studies. However, the therapeutic efficacy varies resulting from the heterogenicity of MSCs. Therefore, purifying the specific MSC subpopulation with specialized function is necessary for their therapeutic applications. Methods The large-scale RNA sequencing analysis was performed to identify potential cell markers for the mouse MSCs. Then, the immune suppression activities of the purified MSC subpopulation were assessed in vitro and in vivo. Results The TNFAIP6 (tumor necrosis factor alpha-induced protein 6) has been identified as a potential cell marker for mouse MSCs, irrespective of tissue origin and laboratory origin. The TNFAIP6+ mouse MSCs showed enhanced immune suppression activities and improved therapeutic effects on the mouse model of acute inflammation, resulting from faster response to immune stimulation. Conclusions Therefore, we have demonstrated that the TNFAIP6+ MSC subpopulation has enhanced immune suppression capabilities.

Unveiling heterogeneity in MSCs: exploring marker-based strategies for defining MSC subpopulations

“…Indeed, the expanded MSCs in vitro are very different from their counterpart in vivo [323]. The MSC expansion strategy would select the cell population which could adapt to these stimuli and stresses [322], indicating the necessity of standardizing the MSC processing procedures and developing a full chemical defined medium [6,[10][11][12]. Therefore, selecting the suitable MSC subpopulations with specific markers based on their functions and applications is necessary and mandatory [6,7].…”

“…And the heterogeneity of MSCs constitutes one of those important barriers before their clinical application [ 6 , 7 ]. Through bioinformatic analysis of the RNA-seq data from different labs and tissues, it is shown that the isolation and expansion procedures induce more heterogeneity than the tissue origin [ 12 ]. It should be noted that purifying and expanding the MSCs in vitro is a kind of stress similar to tissue damage in vivo, which might affect the molecular pathways and functions of MSCs [ 322 ].…”

“…It has been demonstrated that TNFAIP6 (Tumor Necrosis Factor Alpha-Induced Protein 6) is a potential cell marker for mouse MSCs, irrespective of tissue origin and laboratory origin, with higher immune suppression activities and improved therapeutic effects [ 12 ]. However, the membrane expression level of TNFAIP6 is significantly lower than its cytoplasm level [ 12 ]. Indeed, TNFAIP6, also known as TSG6, is a small secreted protein with extracellular matrix remodeling and immunomodulation functions [ 37 ].…”

“…The heterogeneity of MSCs is reflected in different levels, such as the molecular levels (transcriptomics, proteomics, secretomics, and epigenomics), and the function levels (tri-lineage differentiation potentials, immunomodulatory capabilities, and regenerative activities) [2,7,8]. The heterogeneity of MSCs could be induced by various factors including the donor conditions (age, gender, health condition, genetic background, and so on), tissue origin, and the strategies to isolate and expand the MSCs (digestion enzyme, matrix protein, cell culture medium, passage number, and so on) [2,6,7,[9][10][11][12] (Fig. 1).…”

Improved therapeutic consistency and efficacy of CD317+ MSCs through stabilizing TSG6 by PTX3

“…This heterogeneity in MSCs can be attributed to a range of factors, including donor conditions such as age, gender, health status, and genetic background, along with tissue origin and the specific strategies employed for MSC isolation and expansion, encompassing variables like digestion enzymes, matrix proteins, cell culture medium, and passage numbers. These factors collectively contribute to the complexity of achieving consistent and predictable results in MSC-based therapies [ 2 , 6 – 11 ].…”