Human iPSC-derived iMSCs improve bone regeneration in mini-pigs

Abstract

Autologous bone marrow concentrate (BMC) and mesenchymal stem cells (MSCs) have beneficial effects on the healing of bone defects. To address the shortcomings associated with the use of primary MSCs, induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) have been proposed as an alternative. The aim of this study was to investigate the bone regeneration potential of human iMSCs combined with calcium phosphate granules (CPG) in critical-size defects in the proximal tibias of mini-pigs in the early phase of bone healing compared to that of a previously reported autograft treatment and treatment with a composite made of either a combination of autologous BMC and CPG or CPG alone. iMSCs were derived from iPSCs originating from human fetal foreskin fibroblasts (HFFs). They were able to differentiate into osteoblasts in vitro, express a plethora of bone morphogenic proteins (BMPs) and secrete paracrine signaling-associated cytokines such as PDGF-AA and osteopontin. Radiologically and histomorphometrically, HFF-iMSC + CPG transplantation resulted in significantly better osseous consolidation than the transplantation of CPG alone and produced no significantly different outcomes compared to the transplantation of autologous BMC + CPG after 6 weeks. The results of this translational study imply that iMSCs represent a valuable future treatment option for load-bearing bone defects in humans.

Secretome Analysis of Mesenchymal Stem Cell Factors Fostering Oligodendroglial Differentiation of Neural Stem Cells In Vivo

“…Underlying pro-oligodendroglial mechanisms and proteins secreted by MSCs have not yet been deciphered in detail. Although some MSC secretome or proteome data already exist, most of them deal with anti-inflammatory, regenerative, and tumor-promoting properties of MSCs [23][24][25][58][59][60]. Therefore, we applied a quantitative secretome approach for the analysis of MSC-derived proteins with pro-oligodendroglial activity.…”

Pre-Clinical Evaluation of Biological Bone Substitute Materials for Application in Highly Loaded Skeletal Sites

“…Special care should be taken when selecting the breed of pigs, as the vast majority of pig breeds often have excessive body weight and tend to have very high levels of bone density, and hence decreased structural similarity to human bone. Consequently, load-bearing BSM research has also been conducted in mini-and micro-pigs [103,104], as these animals are still very similar to the human condition but weigh less than common pigs [95]. Dogs and humans are qualitatively similar in terms of composition and bone mechanical properties [89,105].…”

Versatility of Induced Pluripotent Stem Cells (iPSCs) for Improving the Knowledge on Musculoskeletal Diseases

“…MSCs derived from iPSCs were found to be comparable to adult MSCs in terms of multipotency even when derived using different protocols [ 134 , 138 , 145 ]. Osteochondral and bone defects treated with iPSCs or differentiated iPSCs on scaffolds did not show differences when compared with adult MSCs transplanted using the same procedures [ 44 , 137 , 142 ]. Jungbluth et al [ 142 ] derived MSCs from iPSCs and combined them with calcium phosphate granules to treat critical bone size defects in minipigs.…”

“…Osteochondral and bone defects treated with iPSCs or differentiated iPSCs on scaffolds did not show differences when compared with adult MSCs transplanted using the same procedures [ 44 , 137 , 142 ]. Jungbluth et al [ 142 ] derived MSCs from iPSCs and combined them with calcium phosphate granules to treat critical bone size defects in minipigs. In this case, iPSC-MSCs on scaffolds improved the osseous consolidation compared with scaffold alone but no significant differences were found when compared with a composite with autologous bone marrow and calcium phosphate.…”

“…Even when no teratomas were found in several in vivo studies using different types of animals [ 60 , 137 , 139 , 140 , 145 , 165 ], there is still some concern [ 166 ]. Some studies reported absence of teratomas when iPSCs were transplanted in vivo as differentiated MSCs [ 139 , 142 , 145 ], lineage-differentiated cells [ 60 , 140 , 143 , 165 ] or even iPSCs seeded on scaffolds [ 137 ]. However, other studies have shown teratoma formation in some animals after treatment with iPSCs seeded on collagen and implanted in osteochondral defects in rats [ 167 ] or after one week of differentiation before implantation in mice [ 164 ].…”