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Human Mesenchymal Stem Cell Derived Exosomes Enhance Cell?Free Bone Regeneration by Altering Their miRNAs Profiles

ABSTRACT: Abstract Implantation of stem cells for tissue regeneration faces significant challenges such as immune rejection and teratoma formation. Cell?free tissue regeneration thus has a potential to avoid these problems. Stem cell derived exosomes do not cause immune rejection or generate malignant tumors. Here, exosomes that can induce osteogenic differentiation of human mesenchymal stem cells (hMSCs) are identified and used to decorate 3D?printed titanium alloy scaffolds to achieve cell?free bone regeneration. Specifically, the exosomes secreted by hMSCs osteogenically pre?differentiated for different times are used to induce the osteogenesis of hMSCs. It is discovered that pre?differentiation for 10 and 15 days leads to the production of osteogenic exosomes. The purified exosomes are then loaded into the scaffolds. It is found that the cell?free exosome?coated scaffolds regenerate bone tissue as efficiently as hMSC?seeded exosome?free scaffolds within 12 weeks. RNA?sequencing suggests that the osteogenic exosomes induce the osteogenic differentiation by using their cargos, including upregulated osteogenic miRNAs (Hsa?miR?146a?5p, Hsa?miR?503?5p, Hsa?miR?483?3p, and Hsa?miR?129?5p) or downregulated anti?osteogenic miRNAs (Hsa?miR?32?5p, Hsa?miR?133a?3p, and Hsa?miR?204?5p), to activate the PI3K/Akt and MAPK signaling pathways. Consequently, identification of osteogenic exosomes secreted by pre?differentiated stem cells and the use of them to replace stem cells represent a novel cell?free bone regeneration strategy. Exosomes secreted from human mesenchymal stem cells (hMSCs) pre?differentiated for a certain period of time can serve as inducers to induce osteogenic differentiation of hMSCs in vitro. They can decorate 3D printed titanium alloy scaffolds, which are further implanted into radial bone defect. They are found to enable the scaffolds to achieve efficient cell?free bone regeneration in vivo.

SUBMITTER: Zhai M

PROVIDER: S-EPMC7539212 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Project description:Bone regeneration poses a significant challenge in the field of tissue engineering, prompting ongoing research to explore innovative strategies for effective bone healing. The integration of stem cells and nanomaterial scaffolds has emerged as a promising approach, offering the potential to enhance regenerative outcomes. This study focuses on the application of a stem cell-laden nanomaterial scaffold designed for bone regeneration in rabbits. The in vivo study was conducted on thirty-six healthy skeletally mature New Zealand white rabbits that were randomly allocated into six groups. Group A was considered the control, wherein a 15 mm critical-sized defect was created and left as such without any treatment. In group B, this defect was filled with a polycaprolactone-hydroxyapatite (PCL + HAP) scaffold, whereas in group C, a PCL + HAP-carboxylated multiwalled carbon nanotube (PCL + HAP + MWCNT-COOH) scaffold was used. In group D, a PCL + HAP + MWCNT-COOH scaffold was used with local injection of bone morphogenetic protein-2 (BMP-2) on postoperative days 30, 45, and 60. The rabbit bone marrow-derived mesenchymal stem cells (rBMSCs) were seeded onto the PCL + HAP + MWCNT-COOH scaffold by the centrifugal method. In group E, an rBMSC-seeded PCL + HAP + MWCNT-COOH scaffold was used along with the local injection of rBMSC on postoperative days 7, 14, and 21. For group F, in addition to the treatment given to group E, BMP-2 was administered locally on postoperative days 30, 45, and 60. Gross observations, radiological observation, scanning electron microscopic assessment, and histological evaluation study showed that group F displayed the best healing properties, followed by group E, group D, group C, and B. Group A showed no healing with ends blunting minimal fibrous tissue. Incorporating growth factor BMP-2 in tissue-engineered rBMSC-loaded nanocomposite PCL + HAP + MWCNT-COOH construct can augment the osteoinductive and osteoconductive properties, thereby enhancing the healing in a critical-sized bone defect. This novel stem cell composite could prove worthy in the treatment of non-union and delayed union fractures in the near future.

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Human Mesenchymal Stem Cell Derived Exosomes Enhance Cell?Free Bone Regeneration by Altering Their miRNAs Profiles

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