Mesenchymal stromal/stem cells (MSCs) are widely utilized in cell therapy because of their robust immunomodulatory and regenerative properties. Their paracrine activity is one of the most important features that contribute to their efficacy. Recently, it has been demonstrated that the production of various factors via extracellular vesicles, especially exosomes, governs the principal efficacy of MSCs after infusion in experimental models. Compared to MSCs themselves, MSC-derived exosomes (MSC-Exos) have provided significant advantages by efficiently decreasing unfavorable adverse effects, such as infusion-related toxicities. MSC-Exos is becoming a promising cell-free therapeutic tool and an increasing number of clinical studies started to assess the therapeutic effect of MSC-Exos in different diseases. In this review, we summarized the ongoing and completed clinical studies using MSC-Exos for immunomodulation, regenerative medicine, gene delivery, and beyond. Additionally, we summarized MSC-Exos production methods utilized in these studies with an emphasis on MSCs source, MSC-Exos isolation methods, characterization, dosage, and route of administration. Lastly, we discussed the current challenges and future directions of exosome utilization in different clinical studies as a novel therapeutic strategy. 

https://stemcellres.biomedcentral.com/counter/pdf/10.1186/s13287-023-03287-7

Mesenchymal stromal/stem cell (MSC)-derived exosomes in clinical trials

As a critical component of the tumor microenvironment (TME), cancer‐associated fibroblasts (CAFs) play important roles in cancer initiation and progression. Well‐known signaling pathways, including the transforming growth factor‐β (TGF‐β), Hedgehog (Hh), Notch, Wnt, Hippo, nuclear factor kappa‐B (NF‐κB), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), mitogen‐activated protein kinase (MAPK), and phosphoinositide 3‐kinase (PI3K)/AKT pathways, as well as transcription factors, including hypoxia‐inducible factor (HIF), heat shock transcription factor 1 (HSF1), P53, Snail, and Twist, constitute complex regulatory networks in the TME to modulate the formation, activation, heterogeneity, metabolic characteristics and malignant phenotype of CAFs. Activated CAFs remodel the TME and influence the malignant biological processes of cancer cells by altering the transcriptional and secretory characteristics, and this modulation partially depends on the regulation of signaling cascades. The results of preclinical and clinical trials indicated that therapies targeting signaling pathways in CAFs demonstrated promising efficacy but were also accompanied by some failures (e.g., NCT01130142 and NCT01064622). Hence, a comprehensive understanding of the signaling cascades in CAFs might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the development of more efficient and safer stroma‐targeted cancer therapies. Here, we review recent advances in studies of signaling pathways in CAFs and briefly discuss some future perspectives on CAF research.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cac2.12392

Signaling pathways in cancer‐associated fibroblasts: recent advances and future perspectives

Abstract Cancer immunotherapy and vaccine development have significantly improved the fight against cancers. Despite these advancements, challenges remain, particularly in the clinical delivery of immunomodulatory compounds. The tumor microenvironment (TME), comprising macrophages, fibroblasts, and immune cells, plays a crucial role in immune response modulation. Nanoparticles, engineered to reshape the TME, have shown promising results in enhancing immunotherapy by facilitating targeted delivery and immune modulation. These nanoparticles can suppress fibroblast activation, promote M1 macrophage polarization, aid dendritic cell maturation, and encourage T cell infiltration. Biomimetic nanoparticles further enhance immunotherapy by increasing the internalization of immunomodulatory agents in immune cells such as dendritic cells. Moreover, exosomes, whether naturally secreted by cells in the body or bioengineered, have been explored to regulate the TME and immune-related cells to affect cancer immunotherapy. Stimuli-responsive nanocarriers, activated by pH, redox, and light conditions, exhibit the potential to accelerate immunotherapy. The co-application of nanoparticles with immune checkpoint inhibitors is an emerging strategy to boost anti-tumor immunity. With their ability to induce long-term immunity, nanoarchitectures are promising structures in vaccine development. This review underscores the critical role of nanoparticles in overcoming current challenges and driving the advancement of cancer immunotherapy and TME modification. 

Nanoparticles in tumor microenvironment remodeling and cancer immunotherapy

http://www.cell.com/article/S1525001622006207/pdf

Cell-Derived Nanovesicle-Mediated Drug Delivery to the Brain: Principles and Strategies for Vesicle Engineering.

Extracellular vesicles: a rising star for therapeutics and drug delivery

Parkinson's disease (PD) is the second most widespread neurodegenerative disorder in the world. It has been reported that exosomes derived from mesenchymal stem cells (MSCs) can contribute to the recovery of PD. However, the underlying mechanism remains poorly defined. In this study, proteomics and time-series analysis showed that exosomes derived from MSCs can keep human brain microvascular endothelial cells (HBMECs) in a transcriptionally active state, which may be beneficial for angiogenesis. Next, we found that MSC-derived exosomes can promote the angiogenesis of HBMECs by increasing the expression of ICAM1, and alleviate the damage caused by 1-methyl-4-phenylpyridinium (MPP+) in these cells. Accordingly, when ICAM1 was knocked down, the tube formation ability of HBMECs was obviously decreased. In addition, ICAM1 was found to promote the angiogenesis of HBMECs by activating the SMAD3 and P38MAPK signaling pathways. In a PD mouse model, MSC-derived exosomes were found to contribute to the recovery of PD by promoting ICAM1-related angiogenesis. These findings demonstrate that the exosome-ICAM1-SMAD3/P38MAPK axis can promote the angiogenesis of HBMECs, with possible therapeutic potential for PD.

MSC-Derived Exosomes can Enhance the Angiogenesis of Human Brain MECs and Show Therapeutic Potential in a Mouse Model of Parkinson's Disease.

Cancer-associated fibroblasts (CAFs) play critical roles in cancer progression by regulating tumor cell proliferation, angiogenesis, and metastasis. Recent studies demonstrated that CAFs induce inhibitory immune cell infiltration and chemotherapy resistance in gastric cancer by activating the NF-κB signaling pathway to secrete IL6, IL8, and other inflammatory factors. Inhibition of the NF-κB signaling pathway in CAFs might be a potential therapeutic strategy in gastric cancer. However, how the NF-κB pathway is activated in CAFs remains unclear. We showed that mesenchymal stem cells (MSCs) differentiated into CAFs, induced by the exosomes derived from gastric cancer cells. During the process of differentiation from MSCs into CAFs, we showed that nuclear PKM2 expression was continuously upregulated and associated with NF-κB P65 acetylation, contributing to P65 nuclear retention in CAFs and constant transcription of IL-6, IL-8, and other inflammatory factors, thus promoting gastric cancer cell proliferation. We showed that NF-κB P65 acetylation was induced by P300. We showed that nuclear PKM2 was derived from exosomes of gastric cancer cell lines and the positive feedback loop induced by PKM2-P65 combination. It is also proved that P300 inhibitors can inhibit tumor proliferation in an AGS subcutaneous xenograft tumor model. Our study showed that gastric cancer cells influence the continuous activation of the NF-κB signaling pathway in CAFs by secreting gastric cancer exosomes containing PKM2, thus inducing abnormal metabolism and inflammation activation. This study provides a new therapeutic target for CAF normalization or deactivation strategies.

/pdf/the-role-of-pkm2-nuclear-translocation-in-the-constant-3pv13oqnfk.pdf

The role of PKM2 nuclear translocation in the constant activation of the NF-κB signaling pathway in cancer-associated fibroblasts.

As an important component of the dynamic tumor microenvironment, mesenchymal stem cells (MSCs) can interact with tumor cells to promote tumor growth. Treatment with tumor cell-derived exosomes can ...

Gastric Cancer Cell-Derived Exosomes Can Regulate the Biological Functions of Mesenchymal Stem Cells by Inducing the Expression of Circular RNA circ_0004303.

Metastasis is the major cause of death in colorectal cancer (CRC) patients. Inhibition of metastasis will prolong the survival of patients with CRC. Cancer cells bring their own soil, cancer-associated fibroblasts (CAFs), to metastasize together, promoting the survival and colonization of circulating cancer cells. However, the mechanism by which CAFs metastasize remains unclear. In this study, CAFs were derived from adipose mesenchymal stem cells (MSCs) after co-culture with CRC cell lines. Transwell assays showed that CAFs have stronger migration and invasion abilities than MSCs. In a nude mouse subcutaneous xenograft model, CAFs metastasized from the primary tumour to the lung and promoted the formation of CRC metastases. The expression of HIF-1α was upregulated when MSCs differentiated into CAFs. Inhibition of HIF-1α expression inhibited the migration and invasion of CAFs. Western blot and ChIP assays were used to identify the genes regulated by HIF-1α. HIF-1α regulated the migration and invasion of CAFs by upregulating miR-210 transcription. Bioinformatics analysis and luciferase reporter assays revealed that miR-210 specifically targeted the 3'UTR of VMP1 and regulated its expression. Downregulation of VMP1 enhanced the migration and invasion of CAFs. In vivo, inhibition of miR-210 expression in CAFs reduced the metastasis of CAFs and tumour cells. Therefore, the HIF-1α/miR-210/VMP1 pathway might regulate the migration and invasion of CAFs in CRC. Inhibition of CAF metastasis might reduce CRC metastasis.

HIF-1α promotes the migration and invasion of cancer-associated fibroblasts by miR-210.

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Papers

MSC-Derived Exosomes can Enhance the Angiogenesis of Human Brain MECs and Show Therapeutic Potential in a Mouse Model of Parkinson's Disease.

The role of PKM2 nuclear translocation in the constant activation of the NF-κB signaling pathway in cancer-associated fibroblasts.

Gastric Cancer Cell-Derived Exosomes Can Regulate the Biological Functions of Mesenchymal Stem Cells by Inducing the Expression of Circular RNA circ_0004303.

HIF-1α promotes the migration and invasion of cancer-associated fibroblasts by miR-210.