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Proteomics analysis of exosomes derived from human umbilical cord mesenchymal stem cells

ABSTRACT: Mesenchymal stem cell-derived exosomes (MSC-Exos), noted for their minimal immunogenicity and robust immunomodulatory potential, have emerged as key regulators of immune cell fate. Nevertheless, a comprehensive understanding of their global impact on human NK cell proliferation and effector function remains elusive. In this study, we employed a standardized ex vivo expansion and exosome-priming system to systematically evaluate the regulatory effects of MSC-Exos on peripheral blood-derived NK cells via flow cytometry, cytotoxicity assays, single-cell transcriptomics, and proteomic profiling. Proteomic profiling identified an enrichment of FcγR-related signaling components within MSC-Exos, suggesting a potential role in enhancing antibody-dependent cellular cytotoxicity (ADCC).Collectively, our findings demonstrate that MSC-Exos bolster NK cell expansion and effector maturation through coordinated immuno-metabolic reprogramming, offering a strategic approach to enhancing the therapeutic efficacy of NK cell-based immunotherapies.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Stem Cell, Cell Culture

DISEASE(S): Disease Free

SUBMITTER: Bu fanyu

LAB HEAD: Xuan Dong

PROVIDER: PXD073707 | Pride | 2026-04-16

REPOSITORIES: Pride

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Project description:Cervical cancer (CC) remains a global health challenge, with chemotherapy resistance and tumor recurrence limiting treatment success. Our study investigated the effects of mesenchymal stem cell-derived exosome (MSC-Exos) pretreatment on chemotherapy sensitivity in 3D spheroids generated from HeLa and SiHa CC cell lines. Proteomic profiling of MSC-Exos revealed key proteins, including ANXA1, ANXA2, EF2, LGALS1, and PKM2, with potential roles in tumor regeneration and chemosensitization. Our findings highlight the context-dependent nature of MSC-Exo activity: while they may promote chemoresistance via drug efflux, metabolic reprogramming, and stress adaptation, they can also enhance chemosensitivity by modulating apoptosis, DNA damage response, and integrin-mediated signaling pathways. Functionally, spheroids pretreated with MSC-Exos exhibited altered responses to paclitaxel in combination with either cisplatin or carboplatin, underscoring the potential of MSC-Exos as modulators of chemotherapy response in CC. In HeLa spheroids, pretreatment with MSC-Exo significantly enhanced chemotherapy-induced cytotoxicity, evidenced by decreased cell viability, increased caspase activity, and upregulation of pro-apoptotic markers such as Bax, suggesting sensitization to apoptosis via chemotherapy. Conversely, SiHa spheroids exhibited variable responses. Although MSC-Exo pretreatment did not sensitize SiHa spheroids to paclitaxel-cisplatin, it improved responsiveness to paclitaxel–carboplatin, particularly in the spheroid core. Molecular analysis revealed upregulated SOX2 expression in SiHa spheroids, indicating partial activation of stemness pathways without full acquisition of a cancer stem cell phenotype. Overall, our findings reveal that MSC-Exo pretreatment exerts cell type- and drug-specific effects in CC spheroids. They enhance chemotherapeutic efficacy in HeLa spheroids and selectively alter drug sensitivity in more resistant SiHa spheroids. The results, therefore, represent promising candidates for engineered exosome-based adjuvant therapies in CC.

Project description:Natural Killer cells (NK), a major constituent of innate immune system, have the ability to kill the transformed and infected cells without prior sensitization; can be put to immunotherapeutic use against various malignancies. NK cells discriminate between normal cells and transformed cells via a balance of inhibitory and activating signals induced by interactions between NK cell receptors and target cell ligands. Present study investigates whether expansion of NK cells could augment their anti-myeloma (MM) activity. For NK cell expansion, peripheral blood mononuclear cells from healthy donors and myeloma patients were co-cultured with irradiated K562 cells transfected with 4-1BBL and membrane-bound IL15 (K562-mb15-41BBL). A genome-wide profiling approach was performed to identify gene expression signature in expanded NK (ENK) cells and non-expanded NK cells isolated from healthy donors and myeloma patients. A specific set of genes involved in proliferation, migration, adhesion, cytotoxicity, and activation were up regulated post expansion, also confirmed by flow cytometry. Exp-NK cells killed both allogeneic and autologous primary MM cells more avidly than non-exp-NK cells in vitro. Multiple receptors, particularly NKG2D, natural cytotoxicity receptors, and DNAM-1 contributed to target lysis, via a perforin mediated mechanism. In summary, vigorous expansion and high anti-MM activity both in vitro and in vivo provide the rationale for testing exp-NK cells in a clinical trial for high risk MM. Differential gene expression profile in expanded natural killer (ENK) cells and non-expanded natural killer (NK) cells from healthy donors and myeloma patients Eight healthy donor and eight myeloma patients were used in the study. Non-expanded natural killer (NK) cells were isolated from PBMCs of healthy donors and myeloma patients. Expanded natural killer (ENK) cells were generated from same set of samples as mentioned in expansion protocol. All ENK and NK cells were used for gene expression profiling.

Project description:Human SARS-CoV-2 and avian IBV are highly contagious and deadly coronaviruses causing devastating respiratory diseases in human and chicken, respectively. Lacking effective therapies exacerbates the disease associated with SARS-CoV-2 and IBV infections. Thus, novel therapeutic agents are in demand for controlling viral transmission and disease progression. Mesenchymal stem cells secreted factors (secretome) proven to be safe and highly efficient alternative to stem cells in mesenchymal stem cell-based therapy (MSCT). The most favorable advantage of secretome is the bypass of the side effects of MSCT that include but not limited to tumorigenesis, immune rejection, and infection. In this study, we aimed to investigate the antiviral activities of human Wharton’s jelly mesenchymal stem cells secretome against SARS-CoV-2 and IBV infection. The half-maximal inhibitory concentrations (IC50), and cytotoxic concentration (CC50) values of hWJ-MSC secretome (hWJ-MSC-S) were determined in Vero-E6 cells. Virucidal, anti-adsorption, and anti-replication mechanisms of hWJ-MSC-S against SARS-CoV-2 and IBV infection were evaluated in vitro. In Ovo anti-IBV activity of hWJ-MSC-S was estimated using Specific pathogen-free (SPF) embryonated chicken eggs (ECEs). The antiviral efficacy of hWJ-MSC-S was determined in terms of reduction in viral infection. Protein composition of hWJ-MSC-S was analyzed by mass spectrometry analysis, and gene ontology of secretome proteins was evaluated. Our data showed hWJ-MSC-S to significantly inhibits infection of human SARS-CoV-2 and avian IBV with very low cytotoxicity and embryotoxicity profile. CC50 value of hWJ-MSC-S in Vero-E6 was 39200 µg/ml. IC50, SI values of hWJ-MSC secretome against SARS-CoV-2 were 166.6 µg/ml, and 235.29, respectively. Similarly, IC50, SI values of hWJ-MSC-S against IBV were 439.9 µg/ml, and 89.11, respectively. hWJ-MSC-S reduced PFU/ml of SARS-CoV-2 and IBV by > 90%. Antiviral mechanistic studies demonstrated that hWJ-MSC-S had >95% and >90% virucidal effects on SARS-CoV-2 and IBV infections, respectively. The anti-replication effect was approximately 87.33% against SARS-CoV-2 infection, and >90% against IBV infection. In ovo model, hWJ-MSC-S significantly inhibited IBV infection. At a concentration of 1000 µg/ml, hWJ-MSC-S reduced IBV titre from 763000 ± 32638 to 38.333 ± 6.0093 EID50/ml (>99% inhibition). Similarly, hWJ-MSC-S reduced IBV titer from 763000 ± 32638 to 1896 ± 926.1 EID50/ml (>97% inhibition) at a concentration of 500 µg/ml. In addition, 250 µg/ml concentration of hWJ-MSC-S reduce IBV titer from 763000 ± 32638 to 20380 ± 2885 EID50/ml (>96% inhibition). LC/MS-MS analysis revealed that biological processes of hWJ-MSC-S proteins were mostly related to Immunomodulatory effect. Collectively, our results not only uncovered the antiviral potency of hWJ-MSC-S against SARS-CoV-2 and IBV, but also described the mechanism by which hWJ-MSC-S inhibit viral infection. These findings could be utilized in future pre-clinical and clinical studies to develop an effective therapeutic against human COVID-19 and avian IB respiratory diseases using hWJ-MSC-S.

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Proteomics analysis of exosomes derived from human umbilical cord mesenchymal stem cells

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