Enhancement of the Therapeutic Capacity of Mesenchymal Stem Cells by Genetic Modification: A Systematic Review

Abstract

Background: The therapeutic capacity of mesenchymal stem cells (also known as mesenchymal stromal cells/MSCs) depends on their ability to respond to the need of the damaged tissue by secreting beneficial paracrine factors. MSCs can be genetically engineered to express certain beneficial factors. The aim of this systematic review is to compile and analyze published scientific literatures that report the use of engineered MSCs for the treatment of various diseases/conditions, to discuss the mechanisms of action, and to assess the efficacy of engineered MSC treatment. Methods:We retrieved all published studies in PubMed/MEDLINE and Cochrane Library on July 27, 2019, without time restriction using the following keywords: "engineered MSC" and "therapy" or "manipulated MSC" and "therapy." In addition, relevant articles that were found during full text search were added. We identified 85 articles that were reviewed in this paper.Results: Of the 85 articles reviewed, 51 studies reported the use of engineered MSCs to treat tumor/cancer/malignancy/metastasis, whereas the other 34 studies tested engineered MSCs in treating non-tumor conditions. Most of the studies reported the use of MSCs in animal models, with only one study reporting a trial in human subjects. Thirty nine studies showed that the expression of beneficial paracrine factors would significantly enhance the therapeutic effects of the MSCs, whereas thirty three studies showed moderate effects, and one study in humans reported no effect. The mechanisms of action for MSC-based cancer treatment include the expression of "suicide genes," induction of tumor cell apoptosis, and delivery of cytokines to induce an immune response against cancer cells. In the context of the treatment of non-cancerous

Comprehensive Profiling of Secretome Formulations from Fetal- and Perinatal Human Amniotic Fluid Stem Cells

“…In this perspective, mesenchymal stromal cells (MSC) have been extensively tested as putative cell candidates. Indeed, MSC and stem/progenitor cells have been engineered and/or stimulated by different preconditioning strategies to enhance their regenerative capacity and secretory potential [ 3 , 4 ], with explicit interest towards the biological relevance of their secreted extracellular vesicles (EVs).…”

The Current Status of Mesenchymal Stromal Cells: Controversies, Unresolved Issues and Some Promising Solutions to Improve Their Therapeutic Efficacy

“…The most common vectors used to modify MSCs are retrovirus, lentivirus, adenovirus and adeno-associated virus (AAV) ( Sage et al, 2016 ). Among the non-viral approaches mRNA lipofectamine-mediated transfection, PEGylated DNA template nanocomposite system, biotinylated MSC, spermin pullulan, hyper-branched polyamidoamine and jetPEI-mediated transfection have been used ( Pawitan et al, 2020 ).…”

“…The overexpression of other factors including VEGF, BMP2, osteogenic molecules (i.e., TGFβ, Cbfa-1, and Osterix), or molecules involved in homing (CXCR4 and CXCL12), etc. have been shown to enhance the MSC capacities ( Pawitan et al, 2020 ). Particularly, enhanced IL-10 production has been intensively tested.…”

“…Engineered MSCs have been also used as anti-tumor therapeutic agents alone or in conjunction with chemotherapeutic drugs ( Pawitan et al, 2020 ). Three strategies have been used: (i) to insert suicide genes that transform non-toxic pro-drugs into cytotoxic molecules; (ii) to use MSCs as vehicles to transport cytokines for enhancing in vivo anti-tumoral immunity or (iii) as agents to kill directly the tumor cells.…”

Cell Interplay in Osteoarthritis

“…Immunotherapy and nanotechnology can help overcome these limitations. At present, genetic engineering techniques, including the use of viral vectors and CRISPR-Cas9 genome editing ( Gerace et al, 2017 ; Pawitan et al, 2020 ), have been proposed to improve the immune regulation of MSCs. The biological scaffold carrying MSCs expressed IL-1Ra under the influence of exogenous doxycycline, which induces inflammation resistance, contributing to the recovery of degenerative articular cartilage, indicating that cell engineering combined with biological materials can enhance the immunomodulatory ability of MSCs ( Glass et al, 2014 ).…”