Mesenchymal stem cells (MSCs) are multipotent stem cells characterized by self-renewal, production of clonal cell populations, and multilineage differentiation. They exist in nearly all tissues and play a significant role in tissue repair and regeneration. Additionally, MSCs possess wide immunoregulatory properties via interaction with immune cells in both innate and adaptive immune systems, leading to immunosuppression of various effector functions. Numerous bioactive molecules secreted by MSCs, particularly cytokines, growth factors, and chemokines, exert autocrine/paracrine effects that modulate the physiological processes of MSCs. These invaluable virtues of MSCs provide new insight into potential treatments for tissue damage and inflammation. In particular, their extensive immunosuppressive properties are being explored for promising therapeutic application in immune disorders. Recently, clinical trials for MSC-mediated therapies have rapidly developed for immune-related diseases following reports from preclinical studies declaring their therapeutic safety and efficacy. Though immunotherapy of MSCs remains controversial, these clinical trials pave the way for their widespread therapeutic application in immune-based diseases. In this review, we will summarize and update the latest research findings and clinical trials on MSC-based immunomodulation.

/pdf/mesenchymal-stem-cell-based-immunomodulation-properties-and-4dafwvam9h.pdf

Mesenchymal Stem Cell-Based Immunomodulation: Properties and Clinical Application

N6-methyladenosine (m6A) is the most abundant epigenetic modification in eukaryotic mRNAs and is essential for multiple RNA processing events during mammalian development and disease control. Here we show that conditional knockout of the m6A methyltransferase Mettl3 in bone marrow mesenchymal stem cells (MSCs) induces pathological features of osteoporosis in mice. Mettl3 loss-of-function results in impaired bone formation, incompetent osteogenic differentiation potential and increased marrow adiposity. Moreover, Mettl3 overexpression in MSCs protects the mice from estrogen deficiency-induced osteoporosis. Mechanistically, we identify PTH (parathyroid hormone)/Pth1r (parathyroid hormone receptor-1) signaling axis as an important downstream pathway for m6A regulation in MSCs. Knockout of Mettl3 reduces the translation efficiency of MSCs lineage allocator Pth1r, and disrupts the PTH-induced osteogenic and adipogenic responses in vivo. Our results demonstrate the pathological outcomes of m6A mis-regulation in MSCs and unveil novel epitranscriptomic mechanism in skeletal health and diseases.

/pdf/mettl3-mediated-m-6-a-rna-methylation-regulates-the-fate-of-xcp1efzfm0.pdf

Mettl3-mediated m 6 A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis

The osteogenic differentiation of mesenchymal stem cells (MSCs) is governed by multiple mechanisms Growing evidence indicates that ubiquitin‐dependent protein degradation is critical for the differentiation of MSCs and bone formation; however, the function of ubiquitin‐specific proteases, the largest subfamily of deubiquitylases, remains unclear Here, we identify USP34 as a previously unknown regulator of osteogenesis The expression of USP34 in human MSCs increases after osteogenic induction while depletion of USP34 inhibits osteogenic differentiation Conditional knockout of Usp34 from MSCs or pre‐osteoblasts leads to low bone mass in mice Deletion of Usp34 also blunts BMP2‐induced responses and impairs bone regeneration Mechanically, we demonstrate that USP34 stabilizes both Smad1 and RUNX2 and that depletion of Smurf1 restores the osteogenic potential of Usp34‐deficient MSCs in vitro  Taken together, our data indicate that USP34 is required for osteogenic differentiation and bone formation

Ubiquitin‐specific protease USP34 controls osteogenic differentiation and bone formation by regulating BMP2 signaling

Bone marrow-derived mesenchymal stem cells (BM-MSCs), the common progenitor cells of adipocytes and osteoblasts, have been recognized as the key mediator during bone formation. Herein, our study aim to investigate molecular mechanisms underlying circular RNA (circRNA) AFF4 (circ_AFF4)-regulated BM-MSCs osteogenesis. BM-MSCs were characterized by FACS, ARS, and ALP staining. Expression patterns of circ_AFF4, miR-135a-5p, FNDC5/Irisin, SMAD1/5, and osteogenesis markers, including ALP, BMP4, RUNX2, Spp1, and Colla1 were detected by qRT-PCR, western blot, or immunofluorescence staining, respectively. Interactions between circ_AFF4 and miR-135a-5p, FNDC5, and miR-135a-5p were analyzed using web tools including TargetScan, miRanda, and miRDB, and further confirmed by luciferase reporter assay and RNA pull-down. Complex formation between Irisin and Integrin αV was verified by Co-immunoprecipitation. To further verify the functional role of circ_AFF4 in vivo during bone formation, we conducted animal experiments harboring circ_AFF4 knockdown, and born samples were evaluated by immunohistochemistry, hematoxylin and eosin, and Masson staining. Circ_AFF4 was upregulated upon osteogenic differentiation induction in BM-MSCs, and miR-135a-5p expression declined as differentiation proceeds. Circ_AFF4 knockdown significantly inhibited osteogenesis potential in BM-MSCs. Circ_AFF4 stimulated FNDC5/Irisin expression through complementary binding to its downstream target molecule miR-135a-5p. Irisin formed an intermolecular complex with Integrin αV and activated the SMAD1/5 pathway during osteogenic differentiation. Our work revealed that circ_AFF4, acting as a sponge of miR-135a-5p, triggers the promotion of FNDC5/Irisin via activating the SMAD1/5 pathway to induce osteogenic differentiation in BM-MSCs. These findings gained a deeper insight into the circRNA-miRNA regulatory system in the bone marrow microenvironment and may improve our understanding of bone formation-related diseases at physiological and pathological levels.

/pdf/circular-rna-aff4-modulates-osteogenic-differentiation-in-bm-135nitcsjb.pdf

Circular RNA AFF4 modulates osteogenic differentiation in BM-MSCs by activating SMAD1/5 pathway through miR-135a-5p/FNDC5/Irisin axis.

As approximately 70% of human breast tumors are estrogen receptor α (ERα)-positive, estrogen and ERα play essential roles in breast cancer development. By interrupting the ERα signaling pathway, endocrine therapy has been proven to be an effective therapeutic strategy. In this study, we identified a mechanism by which Transcription Start Site (TSS)-associated histone H3K27 acetylation signals the Super Elongation Complex (SEC) to regulate transcriptional elongation of the ESR1 (ERα) gene. SEC interacts with H3K27ac on ESR1 TSS through its scaffold protein AFF4. Depletion of AFF4 by siRNA or CRISPR/Cas9 dramatically reduces expression of ESR1 and its target genes, consequently inhibiting breast cancer cell growth. More importantly, a AFF4 mutant which lacks H3K27ac interaction failed to rescue ESR1 gene expression, suggesting H3K27 acetylation at TSS region is a key mark bridging the transition from transcriptional initiation to elongation, and perturbing SEC function can be an alternative strategy for targeting ERα signaling pathway at chromatin level. Gao et al. study the relationship between AFF4 and acetylated histone H3K27 in the context of estrogen receptor alpha signaling. They use a series of pull down assays, genetic backgrounds, and global sequencing analysis and show that AFF4 binds to H2K27ac at promoters and influences the ER alpha signaling and breast cancer cell growth.

/pdf/acetylation-of-histone-h3k27-signals-the-transcriptional-4mp976wzpb.pdf

Acetylation of histone H3K27 signals the transcriptional elongation for estrogen receptor alpha.

AFF1 and AFF4 belong to the AFF (AF4/FMR2) family of proteins, which function as scaffolding proteins linking two different transcription elongation factors, positive elongation factor b (P-TEFb) and ELL1/2, in super elongation complexes (SECs) Both AFF1 and AFF4 regulate gene transcription through elongation and chromatin remodeling However, their function in the osteogenic differentiation of mesenchymal stem cells (MSCs) is unknown In this study, we show that small interfering RNA (siRNA)-mediated depletion of AFF1 in human MSCs leads to increased alkaline phosphatase (ALP) activity, enhanced mineralization and upregulated expression of osteogenic-related genes On the contrary, depletion of AFF4 significantly inhibits the osteogenic potential of MSCs In addition, we confirm that overexpression of AFF1 and AFF4 differentially affects osteogenic differentiation in vitro and MSC-mediated bone formation in vivo Mechanistically, we find that AFF1 regulates the expression of DKK1 via binding to its promoter region Depletion of DKK1 in HA-AFF1-overexpressing MSCs abrogates the impairment of osteogenic differentiation Moreover, we detect that AFF4 is enriched in the promoter region of ID1 AFF4 knockdown blunts the BRE luciferase activity, SP7 expression and ALP activity induced by BMP2 treatment In conclusion, our data indicate that AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs

/pdf/aff1-and-aff4-differentially-regulate-the-osteogenic-1e1br39651.pdf

AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs.

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AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs.