Letter to the Editor: Cell source dictates the effect - a critical consideration for exosome-based cancer therapies

Abstract

Exosomes are increasingly recognized as versatile tools in cancer therapy. Here, we read with great interest the study by Ababneh et al published in the recent issue of World Journal of Stem Cells, which presents a nuanced insight into the complex role of mesenchymal stem cells (MSCs) derived exosomes in cancer. This study crucially demonstrates that the anti-cancer effects of MSCs-exosomes are not universal but are profoundly source-dependent. The finding that exosomes from induced pluripotent stem cell-derived MSCs consistently and potently induce a senescence-like state in aggressive cancer cells, while those from bone marrow MSCs show variable and weaker effects, has several key implications. It underscores that the functional “fingerprint” of an exosome is dependent on its parent cell, and highlights the paramount importance of exosome source selection, moving beyond generic “MSCs-derived exosomes” to specify and compare origins. On this basis, we call for the need for rigorous standardization and functional profiling of exosome preparations to ensure reproducibility and clinical relevance.

Key Words: Exosome; Cell source; Cancer therapies; Mesenchymal stem cells; Induced pluripotent stem cells

Core Tip: Building on the study by Ababneh et al, we emphasize that the anti-cancer effects of mesenchymal stem cells (MSCs) derived exosomes are profoundly source-dependent. The research demonstrates that exosomes from induced pluripotent stem cell-derived MSCs potently induce senescence in aggressive cancer cells, whereas those from bone marrow MSCs show weaker effects. This highlights the critical need to move beyond generic “MSCs-exosome” descriptions. We advocate for rigorous standardization and functional profiling of exosome sources to ensure reproducibility and clinical relevance in future therapies.

TO THE EDITOR

Mesenchymal stem cells (MSCs) are one type of adult stem cells harboring in many tissues[1]. MSCs-derived exosomes are increasingly recognized as versatile tools in tissue regeneration[2] and cancer therapy[3]. They can also function as natural drug delivery vehicles due to their biocompatibility and targeting capabilities[4]. Researchers are actively engineering them to carry chemotherapeutic agents, small interfering RNA, or microRNAs (miRNAs) to selectively kill tumor cells or overcome drug resistance. Additionally, their role in modulating the tumor microenvironment and immune response is a major focus.

Multiple studies have established that exosomes from various sources of MSCs can induce senescence in cancer cells[5], though adverse reports exist[6]. This phenomenon may be mediated by the specific cargo they carry, such as tumor-suppressive miRNAs (e.g., miR-218[7], miR-27a-3p[8]) that inhibit cell cycle progression. This evidence positions exosome-induced senescence as a recognized, non-apoptotic mechanism of tumor growth suppression.

We read with great interest the study by Ababneh et al[9] recently published in the World Journal of Stem Cells presents a fascinating and nuanced insight into the complex role of MSCs-derived exosomes in cancer. The finding that induced pluripotent stem cell-derived MSCs (iMSCs) induce a potent, sustained senescence-like state in aggressive cancer cells, without triggering apoptosis, is particularly significant. The reprogramming and differentiation process that creates iMSCs appears to yield exosomes with a more robust and reliable anti-proliferative cargo, possibly enriched in specific non-coding RNAs or proteins that drive senescence. It positions cellular senescence as a key, and potentially double-edged, therapeutic mechanism. While this senescence can effectively inhibit proliferation, its long-term implications in the tumor microenvironment warrant careful investigation. Furthermore, it highlights the requirement of a deeper mechanistic investigation into the specific molecular cargo - particularly the unique miRNAs, proteins, and lipids - that drive these source-dependent outcomes, such as the potent senescence induction by iMSCs-derived exosomes (iMSCs-Exos). For example, in neurological repair, exosomes from bone marrow MSCs (BM-MSCs-Exos) have been shown to promote neurite outgrowth and functional recovery after stroke, potentially through specific miRNA signatures like miR-133b[10].

More importantly, this study crucially demonstrates that the anti-cancer effects of MSCs-derived exosomes are not universal but are profoundly source-dependent. This is consistent with our previous observation that MSCs from different sources possess different differentiation abilities[11,12] and protein secretion profile[13]. Consistently, some studies have reported multipotency variation between MSCs. Vidal et al[14] reported that equine adipose tissue derived MSCs (AT-MSCs) have less chondrogenic potential than bone marrow MSCs (BM-MSCs). Umbilical cord blood derived MSCs were reported to possess less adipogenic potential than BM-MSCs[15]. This source derived variation also affects the secretion profile of MSCs. Villatoro et al[16] compared the soluble factors and exosomes from cultured canine AT-MSCs and BM-MSCs, and found that AT-MSCs have higher proliferative capacity, whereas BM-MSCs show a significantly higher secretory production of soluble factors. Yoo et al[17] reported that umbilical cord derived MSCs secret higher level of interleukin-6 and interleukin-8 than BM-MSCs and umbilical cord blood derived MSCs. Therefore, it is predictable that MSCs-derived exosomes are highly dependent on their tissue of origin, leading to divergent outcomes across various disease models.

It has to be mentioned that the gene and protein expression profile in exosomes derived from a specific tissue source are likely to mimic their original microenvironment, and may deliver extra benefits in repairing their original source of tissue. In a comparative study[18], cardiomyocytes derived exosomes were more effective than BM-MSCs-Exos in repairing isoproterenol induced ischemic damaged cardiomyocytes. This is proved by another study[19] where AT-MSCs derived exosomes and BM-MSCs-Exos were compared for their therapeutic effect om mouse osteoarthritis model, and found that BM-MSCs-Exos exerted a higher effect to improve osteoarthritis. This source-dependent functional variation, now also highlighted in cancer by the superior senescence-inducing capacity of iMSCs-Exos, firmly establishes that the parental source is a critical determinant of exosome function, necessitating careful selection for specific therapeutic applications.

The finding that iMSCs-Exos consistently and potently induce a senescence-like state in aggressive cancer cells, while BM-MSCs-Exos show variable and weaker effects, has several key implications. First, it definitively establishes that the functional identity of an exosome is inherently determined by its parental cell lineage, moving beyond the simplistic view of exosomes as generic delivery vehicles. The unique microenvironment and epigenetic history of the source cell are directly imprinted onto the exosomal cargo. Specifically, the reprogramming and differentiation process that creates iMSCs appears to yield exosomes with a more robust and reliable anti-proliferative cargo, possibly enriched in specific non-coding RNAs or senescence-associated proteins. Comparative sequencing of non-coding RNAs or protein profiles in the iMSCs-Exos and BM-MSC-Exos may help to identify the underlining mechanism. For example, mir-99b-5p[20] has been reported to play a role in the cell cycle suppression of prostate cancer cells by human BM-MSC-Exos. This suggests that iMSCs represent a uniquely “primed” cellular source for generating therapeutic exosomes with targeted anti-cancer activity.

Second, this finding establishes a critical principle for therapeutic development: The selection of the exosome source is paramount. It is not merely a starting material but a fundamental design parameter that dictates the therapy’s mechanism and efficacy. In this context, iMSCs represent a highly scalable and standardized cell source compared to the inherent donor-to-donor variability of primary BM-MSCs. This offers a promising path towards more consistent, well-characterized exosome therapies, overcoming a major hurdle in clinical translation. However, the therapeutic translation of this finding requires cautious evaluation of potential risks. A critical concern is the senescence-associated secretory phenotype. While senescence halts proliferation, senescence-associated secretory phenotype factors secreted by these stalled cells can paradoxically exacerbate inflammation, remodel the tumor microenvironment, and have potential significant impact on adjacent cells. Therefore, beyond standardizing exosome sources, future work must rigorously profile not just the induction of senescence but also the functional consequences of the senescent state it creates, ensuring therapeutic strategies safely harness this mechanism without unintended pro-tumorigenic effects.

Finally, it underscores the urgent need for rigorous standardization and deep functional profiling of exosome preparations. To ensure reproducibility and clinical relevance, quality control must go beyond mere particle counting and characterization of surface markers. It must include a functional assessment of the biological effect, ensuring that therapeutic applications are built on a precise and mechanistic understanding of the causal relationship between a specific exosome source and its intended biological outcome.