Exosomes secreted from mutant‐HIF‐1α‐modified bone‐marrow‐derived mesenchymal stem cells attenuate early steroid‐induced avascular necrosis of femoral head in rabbit

Abstract

Mesenchymal stem cells (MSCs)-derived exosomes exhibit protective effects on damaged or diseased tissues. Hypoxia-inducible factor 1α (HIF-1α) plays a critical role in bone development. However, HIF-1α is easily biodegradable under normoxic conditions. The bone-marrow-derived mesenchymal stem cells (BMSCs) were transfected with adenovirus carrying triple point-mutations (amino acids 402, 564, and 803) in the HIF-1α coding sequence (CDS). The mutant HIF-1α can efficiently express functional proteins under normoxic conditions. To date, no study has reported the role of exosomes secreted by mutant HIF-1α modified BMSCs in the recovery of the early steroid-induced avascular necrosis of femoral head (SANFH). In this study, we firstly analyzed exosomes derived from BMSCs modified by mutant (BMSC-Exos ) or wild-type HIF-1α (BMSC-Exos ). In vitro, we investigated the osteogenic differentiation capacity of BMSCs modified by BMSC-Exos or BMSC-Exos , and the angiogenesis effects of BMSC-Exos and BMSC-Exos on human umbilical vein endothelial cells (HUVECs). Besides, the healing of the femoral head was also assessed in vivo. We found that the potential of osteogenic differentiation of BMSCs treated with BMSC-Exos was higher than the wild-type group in vitro. In addition, BMSC-Exos stimulated the proliferation, migration, and tube formation of HUVECs in a dose-dependent manner. Compared with the BMSC-Exos or PBS control group, the injection of BMSC-Exos into the necrosis region markedly accelerated the bone regeneration and angiogenesis, which were indicated by the increased trabecular reconstruction and microvascular density. Taken together, our data suggest that BMSC-Exos facilitates the repair of SANFH by enhancing osteogenesis and angiogenesis.

Biomaterials Functionalized with MSC Secreted Extracellular Vesicles and Soluble Factors for Tissue Regeneration

“…[ 194 ] Hypoxia inducible factor (HIF)‐1α overexpression yielded MSC‐CM that enhanced endothelial cell migration, [ 195 ] while HIF‐1α MSC‐EVs enhanced angiogenesis in vitro and in vivo, mediated by EV‐shuttled Jagged 1, [ 196 ] and promoted bone regeneration in a rabbit model of avascular necrosis of the femoral head. [ 197 ] Cartilage tissue regeneration in an osteoarthritis rat model was promoted by delivery of EVs secreted from miR‐140‐5p‐overexpressing MSCs that enhanced cell migration and proliferation. [ 129 ] miRNAs packaged within EVs by genetic manipulation were observed to inhibit fibrosis in several indications.…”

De novo transcriptome assembly of four organs of Collichthys lucidus and identification of genes involved in sex determination and reproduction

“…For CC, unigenes were mainly involved in cell (16,229), cell part (16,151) and membrane (11,815). For MF, binding (16,123) was the most prevalent, followed by nucleic acid binding catalytic activity (10,504) and signal transducer activity (1,974).…”

“…Collichthys lucidus, which belongs to Perciformes, is an economically important fish with small somatotype and usually lives in the benthic zone of coastal waters [1]. It's widely distributed in the middle and western Pacific Ocean, including Japan, Korea and China [2].…”

De novo transcriptome assembly of four organs of Collichthys lucidus and identification of genes involved in sex determination and reproduction

“…Collichthys lucidus, which belongs to perciformes, is a kind of economically important fish with small somatotype usually inhabiting in the benthic zone of coastal waters [ 1]. It is mainly captured in northwestern Pacific that ranges from Kyushu of Japan to the south China sea and makes a major contribution to demersal fish catches, supporting an important commercial fishery [ 2].…”