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1.
Adv Sci (Weinh) ; 7(2): 1902295, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31993293

ABSTRACT

Clinical translation of cell-based products is hampered by their limited predictive in vivo performance. To overcome this hurdle, engineering strategies advocate to fabricate tissue products through processes that mimic development and regeneration, a strategy applicable for the healing of large bone defects, an unmet medical need. Natural fracture healing occurs through the formation of a cartilage intermediate, termed "soft callus," which is transformed into bone following a process that recapitulates developmental events. The main contributors to the soft callus are cells derived from the periosteum, containing potent skeletal stem cells. Herein, cells derived from human periosteum are used for the scalable production of microspheroids that are differentiated into callus organoids. The organoids attain autonomy and exhibit the capacity to form ectopic bone microorgans in vivo. This potency is linked to specific gene signatures mimicking those found in developing and healing long bones. Furthermore, callus organoids spontaneously bioassemble in vitro into large engineered tissues able to heal murine critical-sized long bone defects. The regenerated bone exhibits similar morphological properties to those of native tibia. These callus organoids can be viewed as a living "bio-ink" allowing bottom-up manufacturing of multimodular tissues with complex geometric features and inbuilt quality attributes.

2.
Acta Biomater ; 72: 447-460, 2018 05.
Article in English | MEDLINE | ID: mdl-29626696

ABSTRACT

Rapid neovascularization of a tissue-engineered (TE) construct by the host vasculature is quintessential to warrant effective bone regeneration. This process can be promoted through active induction of angiogenic growth factor secretion or by implementation of in vitro pre-vascularization strategies. In this study, we aimed at optimizing the pro-angiogenic effect of Cobalt (Co2+) to enhance vascular endothelial growth factor (VEGF) expression by human periosteum-derived mesenchymal stem cells (hPDCs). Simultaneously we set out to promote microvascular network formation by co-culturing with human umbilical vein endothelial cells (HUVECs). The results showed that Co2+ treatments (at 50, 100 or 150 µM) significantly upregulated in vitro VEGF expression, but inhibited hPDCs growth and HUVECs network formation in co-cultures. These inhibitory effects were mitigated at lower Co2+ concentrations (at 5, 10 or 25 µM) while VEGF expression remained significantly upregulated and further augmented in the presence of Ascorbic Acid and Dexamethasone possibly through Runx2 upregulation. The supplements also facilitated HUVECs network formation, which was dependent on the quantity and spatial distribution of collagen type-1 matrix deposited by the hPDCs. When applied to hPDCs seeded onto calcium phosphate scaffolds, the supplements significantly induced VEGF secretion in vitro, and promoted higher vascularization upon ectopic implantation in nude mice shown by an increase of CD31 positive blood vessels within the scaffolds. Our findings provided novel insights into the pleotropic effects of Co2+ on angiogenesis (i.e. promoted VEGF secretion and inhibited endothelial network formation), and showed potential to pre-condition TE constructs under one culture regime for improved implant neovascularization in vivo. STATEMENT OF SIGNIFICANT: Cobalt (Co2+) is known to upregulate vascular endothelial growth factor (VEGF) secretion, however it also inhibits in vitro angiogenesis through unknown Co2+-induced events. This limits the potential of Co2+ for pro-angiogenesis of tissue engineered (TE) implants. We showed that Co2+ upregulated VEGF expression by human periosteum-derived cells (hPDCs) but reduced the cell growth, and endothelial network formation due to reduction of col-1 matrix deposition. Supplementation with Ascorbic acid and Dexamethasone concurrently improved hPDCs growth, endothelial network formation, and upregulated VEGF secretion. In vitro pre-conditioning of hPDC-seeded TE constructs with this fine-tuned medium enhanced VEGF secretion and implant neovascularization. Our study provided novel insights into the pleotropic effects of Co2+ on angiogenesis and formed the basis for improving implant neovascularization.


Subject(s)
Cobalt , Human Umbilical Vein Endothelial Cells/metabolism , Implants, Experimental , Mesenchymal Stem Cells/metabolism , Neovascularization, Physiologic/drug effects , Periosteum/metabolism , Vascular Endothelial Growth Factor A/biosynthesis , Adult , Cobalt/chemistry , Cobalt/pharmacology , Coculture Techniques , Female , Human Umbilical Vein Endothelial Cells/cytology , Humans , Male , Mesenchymal Stem Cells/cytology , Periosteum/cytology
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