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Mesenchymal stromal cell-derived extracellular vesicles for regenerative therapy and immune modulation: Progress and challenges toward clinical application.

ABSTRACT: Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have emerged as a promising form of regenerative therapy and immune modulation. Fundamental advances in our understanding of MSCs and EVs have allowed these fields to merge and create potential cell-free therapy options that are cell-based. EVs contain active cargo including proteins, microRNA, and mRNA species that can impact signaling responses in target cells to modify inflammatory and repair responses. Increasing numbers of preclinical studies in animals with various types of injury models have been published that demonstrate the potential impact of MSC-EV therapy. Although the emergence of registered clinical protocols suggests translation to clinical application has already begun, several barriers to more widespread clinical adoption remain. In this review, we highlight the progress made in MSC-derived small EV-based therapy by summarizing aspects pertaining to the starting material for MSC expansion, EV production, and isolation methods, studies from preclinical models that have established a foundation of knowledge to support translation into the patient setting, and potential barriers to overcome on the path to clinical application.

SUBMITTER: Allan D

PROVIDER: S-EPMC6954691 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Mesenchymal stromal cell-derived extracellular vesicles for regenerative therapy and immune modulation: Progress and challenges toward clinical application.

Allan David D Tieu Alvin A Lalu Manoj M Burger Dylan D

Stem cells translational medicine 20190814 1

Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have emerged as a promising form of regenerative therapy and immune modulation. Fundamental advances in our understanding of MSCs and EVs have allowed these fields to merge and create potential cell-free therapy options that are cell-based. EVs contain active cargo including proteins, microRNA, and mRNA species that can impact signaling responses in target cells to modify inflammatory and repair responses. Increasing numb ...[more]

PMID: 31411820

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Project description:Drawing from basic knowledge of stem-cell biology, embryonic development, wound healing, and aging, regenerative medicine seeks to develop therapeutic strategies that complement or replace conventional treatments by actively repairing diseased tissue or generating new organs and tissues. Among the various clinical-translational strategies within the field of regenerative medicine, several can be broadly described as promoting disease resolution indirectly through local or systemic interactions with a patient's cells, without permanently integrating or directly forming new primary tissue. In this review, we focus on such therapies, which we term disease-modulating regenerative therapies (DMRT), and on the extent to which they have been translated into the clinical arena in four distinct areas of nephrology: renovascular disease (RVD), sepsis-associated AKI (SA-AKI), diabetic kidney disease (DKD), and kidney transplantation (KTx). As we describe, the DMRT that has most consistently progressed to human clinical trials for these indications is mesenchymal stem/stromal cells (MSCs), which potently modulate ischemic, inflammatory, profibrotic, and immune-mediated tissue injury through diverse paracrine mechanisms. In KTx, several early-phase clinical trials have also tested the potential for ex vivo-expanded regulatory immune cell therapies to promote donor-specific tolerance and prevent or resolve allograft injury. Other promising DMRT, including adult stem/progenitor cells, stem cell-derived extracellular vesicles, and implantable hydrogels/biomaterials remain at varying preclinical stages of translation for these renal conditions. To date (2021), no DMRT has gained market approval for use in patients with RVD, SA-AKI, DKD, or KTx, and clinical trials demonstrating definitive, cost-effective patient benefits are needed. Nonetheless, exciting progress in understanding the disease-specific mechanisms of action of MSCs and other DMRT, coupled with increasing knowledge of the pathophysiologic basis for renal-tissue injury and the experience gained from pioneering early-phase clinical trials provide optimism that influential, regenerative treatments for diverse kidney diseases will emerge in the years ahead.

Project description:Mesenchymal stromal cells (MSCs) are an attractive option for cell therapy for type 1 diabetes mellitus (DM). These cells can be obtained from many sources, but bone marrow and adipose tissue are the most studied. MSCs have distinct advantages since they are nonteratogenic, nonimmunogenic and have immunomodulatory functions. Insulin-producing cells (IPCs) can be generated from MSCs by gene transfection, gene editing or directed differentiation. For directed differentiation, MSCs are usually cultured in a glucose-rich medium with various growth and activation factors. The resulting IPCs can control chemically-induced diabetes in immune-deficient mice. These findings are comparable to those obtained from pluripotent cells. PD-L1 and PD-L2 expression by MSCs is upregulated under inflammatory conditions. Immunomodulation occurs due to the interaction between these ligands and PD-1 receptors on T lymphocytes. If this function is maintained after differentiation, life-long immunosuppression or encapsulation could be avoided. In the clinical setting, two sites can be used for transplantation of IPCs: the subcutaneous tissue and the omentum. A 2-stage procedure is required for the former and a laparoscopic procedure for the latter. For either site, cells should be transplanted within a scaffold, preferably one from fibrin. Several questions remain unanswered. Will the transplanted cells be affected by the antibodies involved in the pathogenesis of type 1 DM? What is the functional longevity of these cells following their transplantation? These issues have to be addressed before clinical translation is attempted. Graphical Abstract Bone marrow MSCs are isolated from the long bone of SD rats. Then they are expanded and through directed differentiation insulin-producing cells are formed. The differentiated cells are loaded onto a collagen scaffold. If one-stage transplantation is planned, a drug delivery system must be incorporated to ensure immediate oxygenation, promote vascularization and provide some growth factors. Some mechanisms involved in the immunomodulatory function of MSCs. These are implemented either by cell to cell contact or by the release of soluble factors. Collectively, these pathways results in an increase in T-regulatory cells.

Dataset Information

Mesenchymal stromal cell-derived extracellular vesicles for regenerative therapy and immune modulation: Progress and challenges toward clinical application.

Publications

Mesenchymal stromal cell-derived extracellular vesicles for regenerative therapy and immune modulation: Progress and challenges toward clinical application.

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