Genetically Engineered-MSC Therapies for Non-unions, Delayed Unions and Critical-size Bone Defects

Abstract

The normal bone regeneration process is a complex and coordinated series of events involving different cell types and molecules. However, this process is impaired in critical-size/large bone defects, with non-unions or delayed unions remaining a major clinical problem. Novel strategies are needed to aid the current therapeutic approaches. Mesenchymal stem/stromal cells (MSCs) are able to promote bone regeneration. Their beneficial effects can be improved by modulating the expression levels of specific genes with the purpose of stimulating MSC proliferation, osteogenic differentiation or their immunomodulatory capacity. In this context, the genetic engineering of MSCs is expected to further enhance their pro-regenerative properties and accelerate bone healing. Herein, we review the most promising molecular candidates (protein-coding and non-coding transcripts) and discuss the different methodologies to engineer and deliver MSCs, mainly focusing on in vivo animal studies. Considering the potential of the MSC secretome for bone repair, this topic has also been addressed. Furthermore, the promising results of clinical studies using MSC for bone regeneration are discussed. Finally, we debate the advantages and limitations of using MSCs, or genetically-engineered MSCs, and their potential as promoters of bone fracture regeneration/repair.

Modifying MSC Phenotype to Facilitate Bone Healing: Biological Approaches

“…In this regard, methods to expedite the healing of bone defects and fractures has merit. Thus, the concept of gene therapy has entered the realm of bone tissue engineering and repair (Evans, 2010 ; Lu C. H. et al, 2013 ; Balmayor and van Griensven, 2015 ; Evans and Huard, 2015 ; Atasoy-Zeybek and Kose, 2018 ; Ball et al, 2018 ; Betz et al, 2018 ; Bougioukli et al, 2018 ; Shapiro et al, 2018 ; Freitas et al, 2019 ). The advantages of gene delivery include the persistent release of a growth factor(s) or other substance(s) over a period of weeks to months, which is generally longer than with local protein delivery devices.…”

“…On a practical level, gene therapy has been accomplished using different methods including: non-viral chemical and physical methods to deliver DNA or microparticles into cells, gene activated matrices (GAMs) or scaffolds that enable the slow release of genetic material to the surrounding cells, the use of viral vectors to transfer genes into cells in vivo , and genetically engineered autologous or allogeneic cells ex vivo with subsequent delivery of these cells in vivo (Atasoy-Zeybek and Kose, 2018 ; Shapiro et al, 2018 ). All of these methods have been used in preclinical studies to facilitate bone formation, and some are in early clinical trials (see summaries in references D'Mello et al, 2017 ; Atasoy-Zeybek and Kose, 2018 ; Betz et al, 2018 ; Freitas et al, 2019 ). A variety of genes that have been delivered in various ways including BMP-2, BMP-4, BMP-7, HIF-1, lysosomal integral membrane protein-1 (LIMP-1), PTH 1-34, PDGF-B, VEGF, caALK2 (a BMP receptor), Runx2, RANKL, and combinations thereof (D'Mello et al, 2017 ; Atasoy-Zeybek and Kose, 2018 ).…”

Growth Factors in Oral Tissue Engineering: New Perspectives and Current Therapeutic Options

“…Three-dimensional maxillary bone volume recoveries choosing autogenous bone graft is today a stable and predictable treatment option. On the other hand, it has been underlined how the bone collected from the same patient's body areas is usually grafted with postoperative difficulties, biological damages, irritation, or pain at the bone-grafting zone [ 13 – 18 ]. Nowadays, the biomaterials of use for facial bone reconstructions are many and of different derivation; moreover, thanks to the digital; it is possible to calculate the quantity of biomaterial needed or obtain the printing of the biomaterial with the ideal shape [ 19 – 25 ].…”

High Mineralization Capacity of IDG-SW3 Cells in 3D Collagen Hydrogel for Bone Healing in Estrogen-Deficient Mice

“…Bone healing after large-scale bone loss remains a major clinical challenge. Tissue engineering is a simple and effective method for generating solid tissues, and it can be used to produce implantable bone grafts for reconstructive surgery and has great prospects in large-scale bone loss repair ( El-Ghannam, 2005 ; Freitas et al, 2019 ). Three-dimensionally cultured osteogenic cells, such as osteoblasts or bone marrow-derived mesenchymal stem cells (BMSCs) in porous scaffolds, are in a favorable environment for the subsequent regeneration of bone tissue under the required conditions ( Yoshikawa and Myoui, 2005 ; Yuan et al, 2007 ).…”