Membrane particles generated from mesenchymal stromal cells modulate immune responses by selective targeting of pro-inflammatory monocytes

Abstract

Mesenchymal stromal cells (MSC) are a promising therapy for immunological disorders. However, culture expanded MSC are large and get trapped in the capillary networks of the lungs after intravenous infusion, where they have a short survival time. Hypothetically, living cells are a risk for tumor formation. To reduce risks associated with MSC infusion and improve the distribution in the body, we generated membrane particles (MP) of MSC and MSC stimulated with IFN-γ (MPγ). Tracking analysis and electron microscopy indicated that the average size of MP was 120 nm, and they showed a round shape. MP exhibited ATPase, nucleotidase and esterase activity, indicating they are enzymatically active. MP and MPγ did not physically interact with T cells and had no effect on CD4+ and CD8+ T cells proliferation. However, MP and MPγ selectively bound to monocytes and decreased the frequency of pro-inflammatory CD14+CD16+ monocytes by induction of selective apoptosis. MP and MPγ increased the percentage of CD90 positive monocytes, and MPγ but not MP increased the percentage of anti-inflammatory PD-L1 monocytes. MPγ increased mRNA expression of PD-L1 in monocytes. These data demonstrate that MP have immunomodulatory properties and have potential as a novel cell-free therapy for treatment of immunological disorders.

Convergence of Cell Pharmacology and Drug Delivery

“…Collectively, these studies suggest that recognition and immune clearance of MSCs could severely limit bioavailability, thereby greatly reducing therapeutic efficacy and duration of therapeutic activity. An alternative hypothesis, that justifies why in animal studies immunosuppression is observed despite a rapid clearance of MSCs, is that efferocytosis is an essential part of the MoA . Studies have shown that inactive MSCs can be just as effective at inducing tolerance as live MSCs , but recent reports demonstrate that the potency of inactive or apoptotic MSCs is limited .…”

“…Examples of engineering techniques to control in vivo cell pharmacokinetics. Examples of various engineering techniques to improve (A) cell‐based gene therapy to extend duration of protein therapy, (B) targeting cells to local tissue via cell surface engineering , (C) pro‐drug cell therapy concentrates drug action within a microenvironment to minimize systemic exposure and decrease off‐target toxicities , and (D) engineered suicide switches as a safety control of cell therapy.…”

Priming of MSCs with inflammation-relevant signals affects extracellular vesicle biogenesis, surface markers, and modulation of T cell subsets

“…By comparison, INF-EVs exhibited a biomodal size distribution that included a population with size range similar to microvesicles, which bud from the plasma membrane and are between 100nm and 1µm in diameter (45,48). EVs from both IFN-γ and TNF-α/IFN-γ preconditioned MSCs have previously been observed with larger size distributions tending towards the microvesicle size range (22,49). The biogenesis of microvesicles differs from that of exosomes, and their immunomodulatory potency has been shown to be less than that of exosomes (50).…”

“…Our study found very little MSC-EV uptake by CD4 -/CD8cells. However, MSC-EVs were reported to be primarily taken up by monocytes (22) (49). Previous studies investigated MSC-EV uptake by subsets of immune cells but not the differential uptake by effector and regulatory T cells.…”

Mesenchymal stromal cells and their derivatives – putative therapeutics in the management of autoimmune pancreatitis

“…Indeed, MSC derivatives (Fig. 2) have, in some cases, been shown to be as therapeutically beneficial as living MSCs [30–33], but have the advantage of being able to pass easily through the circulatory system.…”