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Abstract
Growth factors in serum-free conditioned media from human bone marrow-derived mesenchymal stem cells (MSC-CM) are known to be effective in bone regeneration. However, the secretomes in MSC-CM that act as active ingredients for bone regeneration, as well as their mechanisms, remains unclear. Exosomes, components of MSC-CM, provide the recipient cells with genetic information and enhance the recipient cellular paracrine stimulation, which contributes to tissue regeneration. We hypothesized that MSC-CM-derived exosomes (MSC-Exo) promoted bone regeneration, and that angiogenesis was a key step. Here, we prepared an MSC-Exo group, MSC-CM group, and Exo-antiVEGF group (MSC-Exo with angiogenesis inhibitor), and examined the osteogenic and angiogenic potential in MSCs. Furthermore, we used a rat model of calvaria bone defect and implanted each sample to evaluate bone formation weekly, until week 4 after treatment. Results showed that MSC-Exo enhanced cellular migration and osteogenic and angiogenic gene expression in MSCs compared to that in other groups. In vivo, early bone formation by MSC-Exo was also confirmed. Two weeks after implantation, the newly formed bone area was 31.5 ± 6.5% in the MSC-Exo group while those in the control and Exo-antiVEGF groups were 15.4 ± 4.4% and 8.7 ± 1.1%, respectively. Four weeks after implantation, differences in the area between the MSC-Exo group and the Exo-antiVEGF or control groups were further broadened. Histologically, notable accumulation of osteoblast-like cells and vascular endothelial cells was observed in the MSC-Exo group; however, fewer cells were found in the Exo-antiVEGF and control groups.In conclusion, MSC-Exo promoted bone regeneration during early stages, as well as enhanced angiogenesis. Considering the tissue regeneration with transplanted cells and their secretomes, this study suggests that exosomes might play an important role, especially in angiogenesis.
Highlights
Stem cell-based therapy is a potent tool in regenerative medicine; mesenchymal stem cells (MSCs) are of special interest, given their multipotency, that is, the ability to differentiate into different cell lineages like osteoblasts [1, 2]
Katagiri et al showed that vascular endothelial growth factor (VEGF) acts as an effective growth factor for bone regeneration induced by MSC-CM through enhancing the migration of endogenous vascular endothelial and stem cells [21]; they performed the first-in-human study of alveolar bone regeneration with good clinical outcomes [22]
Vascular endothelial cells and blood vessels were observed well around the newly formed bone in the MSC-CM-derived exosomes (MSC-Exo) group following immunofluorescence staining for CD31. These results indicated that MSC-Exo give the recipient cells some information related to angiogenesis and/or bone regeneration, which leads the recipient cells to activate the secretion of VEGF and osteogenesis-related paracrine factors
Summary
Stem cell-based therapy is a potent tool in regenerative medicine; mesenchymal stem cells (MSCs) are of special interest, given their multipotency, that is, the ability to differentiate into different cell lineages like osteoblasts [1, 2]. MSCs from multiple tissues have been reported to enhance bone regeneration in various models [3,4,5,6] and stem cell-based therapies have been applied clinically to yield good results [7,8,9]. As the secretomes from MSCs contain various factors exerting several biological effects, they are expected to be applied clinically and provide novel strategies for regenerative medicine [18, 19]. Katagiri et al showed that VEGF acts as an effective growth factor for bone regeneration induced by MSC-CM through enhancing the migration of endogenous vascular endothelial and stem cells [21]; they performed the first-in-human study of alveolar bone regeneration with good clinical outcomes [22]. Understanding the molecular events that are regulated by secretomes will help contribute to a better understanding of tissue regeneration
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