Exosomes Secreted from Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Prevent Osteonecrosis of the Femoral Head by Promoting Angiogenesis

Abstract

Background: Local ischemia is the main pathological performance in osteonecrosis of the femoral head (ONFH). There is currently no effective therapy to promote angiogenesis in the femoral head. Recent studies revealed that exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells (iPS-MSC-Exos) have great therapeutic potential in ischemic tissues, but whether they could promote angiogenesis in ONFH has not been reported, and little is known regarding the underlying mechanism.Methods: iPS-MSC-Exos were intravenously injected to a steroid-induced rat osteonecrosis model. Samples of the femoral head were obtained 3 weeks after all the injections. The effects were assessed by measuring local angiogenesis and bone loss through histological and immunohistochemical (IHC) staining, micro-CT and three-dimensional microangiography. The effects of exosomes on endothelial cells were studied through evaluations of proliferation, migration and tube-forming analyses. The expression levels of angiogenic related PI3K/Akt signaling pathway of endothelial cells were evaluated following stimulation of iPS-MSC-Exos. The promoting effects of exosomes were re-evaluated following blockade of PI3K/Akt.Results: The in vivo study revealed that administration of iPS-MSC-Exos significantly prevented bone loss, and increased microvessel density in the femoral head compared with control group. We found that iPS-MSC-Exos significantly enhanced the proliferation, migration and tube-forming capacities of endothelial cells in vitro. iPS-MSC-Exos could activate PI3K/Akt signaling pathway in endothelial cells. Moreover, the promoting effects of iPS-MSC-Exos were abolished after blockade of PI3K/Akt on endothelial cells.Conclusions: Our findings suggest that transplantation of iPS-MSC-Exos exerts a preventative effect on ONFH by promoting local angiogenesis and preventing bone loss. The promoting effect might be attributed to activation of the PI3K/Akt signaling pathway on endothelial cells. The data provide the first evidence for the potential of iPS-MSC-Exos in treating ONFH.

Impaired Bone Regenerative Effect of Exosomes Derived from Bone Marrow Mesenchymal Stem Cells in Type 1 Diabetes

“…It has been reported that the major challenge after graft implantation is the maintenance of cell viability in the graft core, which depends on rapid angiogenesis within the tissue‐engineered implants . Researchers have demonstrated that exosomes can stimulate angiogenesis in bone, which is an important mechanism for stimulating bone regeneration . Consistent with previous studies, we found that both dBMSC‐exos and nBMSC‐exos could enhance the angiogenic activity of HUVECs and promote neovascularization in rat calvarial defects.…”

MicroRNA‐31a‐5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment

“…Targeting these exosomes, which act as important communicators between cells, may emerge as a new therapeutic approach for osteoporosis (Liu et al., 2017; Long et al., 2017; Nakano et al., 2016). In this study, we used antagomiR‐31a‐5p, which was injected into the bone marrow microenvironment, to decrease miR‐31a‐5p expression in the bone marrow microenvironment of osteoporotic rats.…”

Extracellular Vesicles Secreted by Human Urine-Derived Stem Cells Promote Ischemia Repair in a Mouse Model of Hind-Limb Ischemia

“…We found that iMSCs-EVs alleviated hind-limb ischemic injury [27], hepatic IR injury [42] and osteoarthritis [43]. Moreover, iMSCs-EVs also prevented osteonecrosis of the femoral head [44] and enhanced bone regeneration [45,46] and cutaneous wound healing [47]. Based on these findings, we used iMSCs-EVs particles administered at the abovementioned concentration as a positive control in experiments designed to detect the effects of the USCs-EVs on ischemic hind-limb repair.…”