Enhanced osteoblastic differentiation and bone formation in co-culture of human bone marrow mesenchymal stromal cells and peripheral blood mononuclear cells with exogenous VEGF

Joensuu, Katriina; Uusitalo-Malmivaara, Lotta; Alm, Jessica J.; Aro, Hannu T.; Hentunen, Teuvo; Heino, Terhi J.

doi:10.1016/j.otsr.2015.01.014

Cited by 17 publications

(19 citation statements)

References 27 publications

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“…The results of this study also showed that KLF2 + stemness‐maintained hMSCs enhanced osteogenesis more effectively in long‐term culture. Several previous studies have investigated the osteogenic effect between endothelial and osteoblastic cells and identified the crucial role of VEGF . Indeed, VEGF‐A was shown to act as a pivotal regulator in angiogenesis by specific binding to cell‐surface receptors, and also to play an essential role in bone formation .…”

Section: Discussionmentioning

confidence: 99%

“…Several previous studies have investigated the osteogenic effect between endothelial and osteoblastic cells and identified the crucial role of VEGF. 33,[42][43][44] Indeed, VEGF-A was shown to act as a pivotal regulator in angiogenesis by specific binding to cell-surface receptors, 24,45 and also to play an essential role in bone formation. [46][47][48] Previous studies examined the roles of VEGF both in vivo and in vitro and showed that blocking the action of VEGF inhibited osteogenesis.…”

Section: Stemness-and Osteogenesis-related Gene-expression Profiles Inmentioning

confidence: 99%

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KLF2+ stemness maintains human mesenchymal stem cells in bone regeneration

Zhou

Liu

et al. 2019

Stem Cells

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Mesenchymal stem cells (MSCs), which are undifferentiated stem cells with the property of stemness and the potential to differentiate into multiple lineages, including osteoblasts, have attracted a great deal of attention in bone tissue engineering. Consistent with the heterogeneity of MSCs, various surface markers have been used. However, it is still unclear which markers of MSCs are best for cell amplification in vitro and later bone regeneration in vivo. Krüppel‐like Factor 2 (KLF2) is an important indicator of the stemness of human MSCs (hMSCs) and as early vascularization is also critical for bone regeneration, we used KLF2 as a novel in vitro marker for MSCs and investigated the angiogenesis and osteogenesis between KLF2+ MSCs and endothelial cells (ECs). We found a synergistic interaction between hMSCs and human umbilical vein ECs (HUVECs) in that KLF2+ stemness‐maintained hMSCs initially promoted the angiogenesis of HUVECs, which in turn more efficiently stimulated the osteogenesis of hMSCs. In fact, KLF2+ hMSCs secreted angiogenic factors initially, with some of the cells then differentiating into pericytes through the PDGF‐BB/PDGFR‐β signaling pathway, which improved blood vessel formation. The matured HUVECs in turn synergistically enhanced the osteogenesis of KLF2+ hMSCs through upregulated vascular endothelial growth factor. A three‐dimensional coculture model using cell‐laden gelatin methacrylate (GelMA) hydrogel further confirmed these results. This study provides insight into the stemness‐directed synergistic interaction between hMSCs and HUVECs, and our results will have a profound impact on further strategies involving the application of KLF2+ hMSC/HUVEC‐laden GelMA hydrogel in vascular network bioengineering and bone regeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Stemness-and Osteogenesis-related Gene-expression Profiles Inmentioning

confidence: 99%

KLF2+ stemness maintains human mesenchymal stem cells in bone regeneration

Zhou

Liu

et al. 2019

Stem Cells

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“…[6][7][8][9] Improved engineered vasculature would allow ischemic and traumatic tissue defects to be treated more effectively and efficiently. [9][10][11][12][13] The insulin super-family is composed of 10 members in mammals, insulin, 2 insulin-like growth factors, 3 relaxin proteins, and 4 insulinlike peptides.…”

Section: Vascular Endothelial Growth Factor (Vegf) a And Fibroblast mentioning

confidence: 99%

Enhancing engineered vascular networks in vitro and in vivo: The effects of IGF1 on vascular development and durability

et al. 2017

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Objectives: Creation of functional, durable vasculature remains an important goal within the field of regenerative medicine. Engineered biological vasculature has the potential to restore or improve human tissue function. We hypothesized that the pleotropic effects of insulin-like growth factor 1 (IGF1) would enhance the engineering of capillary-like vasculature. Results: IGF1 supplementation significantly enhanced de novo vasculogenesis both in vitro and in vivo. Effects were long-term as they lasted the duration of the study period, and included network density, vessel length, and diameter. Bifurcation density was not affected. However, the highest concentrations of IGF1 tested were either ineffective or even deleterious. Sustained IGF1 delivery was required in vivo as the inclusion of recombinant IGF1 protein had minimal impact.Conclusion: IGF1 supplementation can be used to produce neovasculature with significantly enhanced network density and durability. Its use is a promising methodology for engineering de novo vasculature to support regeneration of functional tissue.

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“…In addition to MNC‐derived EPCs, MSCs have been shown to differentiate into endothelial cells (Table ). In a previous study, MSCs cultured with exogenous VEGF did not differentiate into endothelial cells (Joensuu et al, ) and the sprouting tube‐forming cells in the cocultures were positive for TRACP, an enzyme, which is expressed by the cells of monocyte‐lineage (Joensuu et al, ) indicating that endothelial cells in the MSC‐MNC cocultures probably differentiated from MNC‐derived EPCs instead of MSCs. However, the origin of each mature cell type has not been fully demonstrated in the current study.…”

Section: Discussionmentioning

confidence: 90%

“…It was previously shown that PB-MNCs can differentiate into endothelial cells in MSC-MNC cocultures without exogenously supplied growth factors (Joensuu et al, 2011) and data have demonstrated that MSCs produce proangiogenic factors, such as VEGF and fibroblast growth factor 2 (FGF-2) in a differentiation-dependent manner (Hoch, Binder, Genetos, & Leach, 2012). By contrast, recent results show that in MSC-MNC cocultures the osteoblastic differentiation of human BM-MSCs is enhanced and further potentiated by exogenous VEGF (Joensuu et al, 2015). Taken together, all these data suggest isolated from a 5-ml aspirate of iliac bone marrow from a healthy donor.…”

mentioning

confidence: 99%

Angiogenic potential of human mesenchymal stromal cell and circulating mononuclear cell cocultures is reflected in the expression profiles of proangiogenic factors leading to endothelial cell and pericyte differentiation

Joensuu

Uusitalo‐Kylmälä

Hentunen

et al. 2017

J Tissue Eng Regen Med

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Endothelial progenitors found among the peripheral blood (PB) mononuclear cells (MNCs) are interesting cells for their angiogenic properties. Mesenchymal stromal cells (MSCs) in turn can produce proangiogenic factors as well as differentiate into mural pericytes, making MSCs and MNCs an attractive coculture setup for regenerative medicine. In this study, human bone marrow-derived MSCs and PB-derived MNCs were cocultured in basal or osteoblastic medium without exogenously supplied growth factors to demonstrate endothelial cell, pericyte and osteoblastic differentiation. The expression levels of various proangiogenic factors, as well as endothelial cell, pericyte and osteoblast markers in cocultures were determined by quantitative polymerase chain reaction. Immunocytochemistry for vascular endothelial growth factor receptor-1 and α-smooth muscle actin as well as staining for alkaline phosphatase were performed after 10 and 14 days. Messenger ribonucleic acid expression of endothelial cell markers was highly upregulated in both basal and osteoblastic conditions after 5 days of coculture, indicating an endothelial cell differentiation, which was supported by immunocytochemistry for vascular endothelial growth factor receptor-1. Stromal derived factor-1 and vascular endothelial growth factor were highly expressed in MSC-MNC coculture in basal medium but not in osteoblastic medium. On the contrary, the expression levels of bone morphogenetic protein-2 and angiopoietin-1 were significantly higher in osteoblastic medium. Pericyte markers were highly expressed in both cocultures after 5 days. In conclusion, it was demonstrated endothelial cell and pericyte differentiation in MSC-MNC cocultures both in basal and osteoblastic medium indicating a potential for neovascularization for tissue engineering applications.

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Enhanced osteoblastic differentiation and bone formation in co-culture of human bone marrow mesenchymal stromal cells and peripheral blood mononuclear cells with exogenous VEGF

Cited by 17 publications

References 27 publications

KLF2+ stemness maintains human mesenchymal stem cells in bone regeneration

KLF2+ stemness maintains human mesenchymal stem cells in bone regeneration

Enhancing engineered vascular networks in vitro and in vivo: The effects of IGF1 on vascular development and durability

Angiogenic potential of human mesenchymal stromal cell and circulating mononuclear cell cocultures is reflected in the expression profiles of proangiogenic factors leading to endothelial cell and pericyte differentiation

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