Concise Review: MSC-Derived Exosomes for Cell-Free Therapy

Abstract

Mesenchymal stem cell transplantation is undergoing extensive evaluation as a cellular therapy in human clinical trials. Because MSCs are easily isolated and amenable to culture expansion in vitro there is a natural desire to test MSCs in many diverse clinical indications. This is exemplified by the rapidly expanding literature base that includes many in vivo animal models. More recently, MSCderived extracellular vesicles (EVs), which include exosomes and microvesicles (MV), are being examined for their role in MSC-based cellular therapy. These vesicles are involved in cell-to-cell communication, cell signaling, and altering cell or tissue metabolism at short or long distances in the body. The exosomes and MVs can influence tissue responses to injury, infection, and disease. MSC-derived exosomes have a content that includes cytokines and growth factors, signaling lipids, mRNAs, and regulatory miRNAs. To the extent that MSC exosomes can be used for cell-free regenerative medicine, much will depend on the quality, reproducibility, and potency of their production, in the same manner that these parameters dictate the development of cell-based MSC therapies. However, the MSC exosome's contents are not static, but rather a product of the MSC tissue origin, its activities and the immediate intercellular neighbors of the MSCs. As such, the exosome content produced by MSCs appears to be altered when MSCs are cultured with tumor cells or in the in vivo tumor microenvironment. Therefore, careful attention to detail in producing MSC exosomes may provide a new therapeutic paradigm for cell-free MSC-based therapies with decreased risk. STEM CELLS 2017;35:851-858 SIGNIFICANCE STATEMENTMesenchymal stem/stromal cells (MSCs) are being exploited as an experimental therapy for a variety of human diseases. Current dogma indicates that MSCs ameliorate disease via secretion of paracrine acting factors that limit inflammation, reprogram immune cells, and activate endogenous repair pathways. Recent studies indicate that MSCs also produce extra-cellular vesicles of varying sizes including exosomes that carry as cargo mRNAs, microRNAs, and proteins, and that horizontal transfer of this cargo induces nonautonomous changes that are therapeutic. This manuscript reviews evidence that MSC-derived microvesicles/exosomes function as paracrine mediators in tissue repair and recapitulate to a large extent the therapeutic effects of parental MSCs. It also discusses their role in reprogramming endogenous MSCs to generate a self-reinforcing malignant niche.

Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

“…Recent studies showed that extracellular vesicles (EVs)/exosomes alone contributed to the therapeutic effects of MSCs in multiple animal models, such as those for ischemic stroke [16,58,59], acute kidney injury [60] and traumatic brain injury [17]. Exosomes comprise one of the main subclasses of EVs and are considered the most promising therapeutic mediator of MSC function by altering the activity of target cells via horizontal transfer of mRNAs, microRNAs, and proteins [61]. Compared with factors in the absence of membrane packaging, exosomes are more stable and capable of targeting inflammatory sites due to their enhanced permeability and retention effects [62,63].…”

Differentiation of Human Tonsil-Derived Mesenchymal Stem Cells into Schwann-Like Cells Improves Neuromuscular Function in a Mouse Model of Charcot-Marie-Tooth Disease Type 1A

“…As tonsillar tissues are discarded after surgery, the isolation of stem cells from these discarded tissues offers another valuable means of recycling human tissue for stem cell therapy [20,23]. In addition, the T-MSCs have MSC characteristics and are known to secrete various cytokines [27], growth factors [28], and exosomes [29] considered suitable for cell therapy. The T-MSCs show excellent immune modulation activity and no immunologic problems even when the T-MSCs were combined from three independent donors [23].…”

Human mesenchymal stem cell-derived iron oxide exosomes allow targeted ablation of tumor cells via magnetic hyperthermia

“…21 The discovery of MSC-derived exosomes that act in a paracrine/endocrine fashion is an important step toward cell-free MSC therapy. 22 MSCs and their exosomes are known to recognize tumors and metastases as wounds, migrate to them and integrate into the tumor stroma. Stoff-Khalili et al have shown that intravenous injection of human MSCs loaded with conditionally replicating adenoviruses targeted MDA-MB-231 mouse model of metastatic breast cancer in vivo.…”