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Engineering stem cells to produce exosomes with enhanced bone regeneration effects: an alternative strategy for gene therapy

Li, Feiyang, Wu, Jun, Li, Daiye, Hao, Liuzhi, Li, Yanqun, Yi, Dan, Yeung, Kelvin W. K., Chen, Di, Lu, William W., Pan, Haobo, Wong, Tak Man, Zhao, Xiaoli·2022·Journal of Nanobiotechnology
DOI 10.1186/s12951-022-01347-3PMC PMC8922796
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Abstract

Background: Exosomes derived from stem cells have been widely studied for promoting regeneration and reconstruction of multiple tissues as “cell-free” therapies. However, the applications of exosomes have been hindered by limited sources and insufficient therapeutic potency. Results: In this study, a stem cell-mediated gene therapy strategy is developed in which mediator mesenchymal stem cells are genetically engineered by bone morphogenetic protein-2 gene to produce exosomes (MSC-BMP2-Exo) with enhanced bone regeneration potency. This effect is attributed to the synergistic effect of the content derived from MSCs and the up-regulated BMP2 gene expression. The MSC-BMP2-Exo also present homing ability to the injured site. The toxic effect of genetical transfection vehicles is borne by mediator MSCs, while the produced exosomes exhibit excellent biocompatibility. In addition, by plasmid tracking, it is interesting to find a portion of plasmid DNA can be encapsulated by exosomes and delivered to recipient cells. Conclusions: In this strategy, engineered MSCs function as cellular factories, which effectively produce exosomes with designed and enhanced therapeutic effects. The accelerating effect in bone healing and the good biocompatibility suggest the potential clinical application of this strategy. Graphical Abstract:

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Fig.1 HMSCs were genetically engineered by upregulating BMP2 gene expression. a A schematic illustration of genetically engineering hMSCs by liposome mediated BMP2 gene delivery. b, c Fluorescent images of hMSCs transfected by liposome/pGFP-BMP2 plasmid, and transfection efficiency was analyzed by flow cytometry, Scale bar: 100 μm. d mRNA expressions of osteogenic differentiation-related markers (BMP2, Runx2, OSX, ALP, BSP, OPN) in hMSCs were analyzed by qRT-PCR after transfection. Untransfected hMSCs were detected as control, n = 3. *p < 0.05, **p < 0.01
Fig.1 HMSCs were genetically engineered by upregulating BMP2 gene expression. a A schematic illustration of genetically engineering hMSCs by liposome mediated BMP2 gene delivery. b, c Fluorescent images of hMSCs transfected by liposome/pGFP-BMP2 plasmid, and transfection efficiency was analyzed by flow cytometry, Scale bar: 100 μm. d mRNA expressions of osteogenic differentiation-related markers (BMP2, Runx2, OSX, ALP, BSP, OPN) in hMSCs were analyzed by qRT-PCR after transfection. Untransfected hMSCs were detected as control, n = 3. *p < 0.05, **p < 0.01CC BY · PubMed Central
Fig. 2 BMP2 gene engineering altered the internal mRNA content of derived exosomes. a A schematic illustration of exosomes harvest after hMSCs genetically engineering. b The morphology of MSC-Exo and MSC-BMP2-Exo was observed by TEM. Scale bar: 100 nm. c Size distributions of exosomes were determined by nanoparticle tracking analysis. d Exosomal markers CD63, CD9 and TSG101 in cell and exosome lysates were detected by western blot. e The internal mRNA expressions of osteogenic differentiation-related genes in MSC-Exo, MSC-OB-Exo and MSC-BMP2-Exo were analyzed by qRT-PCR, including BMP2, Runx2, OSX, ALP, BSP and OPN, n = 3. *p < 0.05, **p < 0.01
Fig. 2 BMP2 gene engineering altered the internal mRNA content of derived exosomes. a A schematic illustration of exosomes harvest after hMSCs genetically engineering. b The morphology of MSC-Exo and MSC-BMP2-Exo was observed by TEM. Scale bar: 100 nm. c Size distributions of exosomes were determined by nanoparticle tracking analysis. d Exosomal markers CD63, CD9 and TSG101 in cell and exosome lysates were detected by western blot. e The internal mRNA expressions of osteogenic differentiation-related genes in MSC-Exo, MSC-OB-Exo and MSC-BMP2-Exo were analyzed by qRT-PCR, including BMP2, Runx2, OSX, ALP, BSP and OPN, n = 3. *p < 0.05, **p < 0.01CC BY · PubMed Central
Fig. 3 MSC-BMP2-Exo exhibited excellent cellular uptake efficiency and biocompatibility. a Fluorescent microscopic image showed the cellular internalization of MSC-BMP2-Exo and MSC-Exo by recipient cells after overnight incubation. Exosomes were stained by Dio with green fluorescent, Scale bar: 20 μm. b Flow cytometry analysis of Dio-labeled exosomes engulfed by recipient cells. c Ratios of recipient cells that had engulfed MSC-BMP2-Exo or MSC-Exo. Cells cultured in normal medium without exosomes were also detected as control group, n = 3. d Cell viability of hMSCs incubated with exosomes and Lipo/pBMP2 complex was determined by CCK-8 assay, n = 6. *p < 0.05, **p < 0.01, ***p < 0.001
Fig. 3 MSC-BMP2-Exo exhibited excellent cellular uptake efficiency and biocompatibility. a Fluorescent microscopic image showed the cellular internalization of MSC-BMP2-Exo and MSC-Exo by recipient cells after overnight incubation. Exosomes were stained by Dio with green fluorescent, Scale bar: 20 μm. b Flow cytometry analysis of Dio-labeled exosomes engulfed by recipient cells. c Ratios of recipient cells that had engulfed MSC-BMP2-Exo or MSC-Exo. Cells cultured in normal medium without exosomes were also detected as control group, n = 3. d Cell viability of hMSCs incubated with exosomes and Lipo/pBMP2 complex was determined by CCK-8 assay, n = 6. *p < 0.05, **p < 0.01, ***p < 0.001CC BY · PubMed Central
Fig. 4 MSC-BMP2-Exo promoted osteogenic differentiation of recipient hMSCs in vitro. a Osteogenic differentiation-related mRNA expressions of hMSCs, including BMP2, Runx2, OSX and ALP, were analyzed by qRT-PCR after 5 days of culture, n = 3. Cells were cultured in normal culture medium (control group), differentiation medium (OB group), differentiation medium supplemented with MSC-Exo (MSC-Exo group), and differentiation medium supplemented with MSC-BMP2-Exo (MSC-BMP2-Exo group). b Western blot analysis of recipient cells on the protein expression of Runx2 and OSX after 7 days of culture. Loading control was β-actin. c ALP and alizarin red staining of hMSCs under different treatment after 14 and 21 days of culture. Upper graph: ALP staining, lower graph: alizarin red staining. d Alizarin red staining was quantified by dissolving calcium nodules with 10% hexadecylpyridinium chloride monohydrate solution, n = 3. *p < 0.05, **p < 0.01, ***p < 0.001
Fig. 4 MSC-BMP2-Exo promoted osteogenic differentiation of recipient hMSCs in vitro. a Osteogenic differentiation-related mRNA expressions of hMSCs, including BMP2, Runx2, OSX and ALP, were analyzed by qRT-PCR after 5 days of culture, n = 3. Cells were cultured in normal culture medium (control group), differentiation medium (OB group), differentiation medium supplemented with MSC-Exo (MSC-Exo group), and differentiation medium supplemented with MSC-BMP2-Exo (MSC-BMP2-Exo group). b Western blot analysis of recipient cells on the protein expression of Runx2 and OSX after 7 days of culture. Loading control was β-actin. c ALP and alizarin red staining of hMSCs under different treatment after 14 and 21 days of culture. Upper graph: ALP staining, lower graph: alizarin red staining. d Alizarin red staining was quantified by dissolving calcium nodules with 10% hexadecylpyridinium chloride monohydrate solution, n = 3. *p < 0.05, **p < 0.01, ***p < 0.001CC BY · PubMed Central
Fig. 5 MSC-BMP2-Exos expedited bone regeneration through BMP2/Smad pathway. a 8-week-old male C57BL/6 mice were used for animal study. Holes with diameters of 1 mm were created at lateral epicondyle of right distal femur. At each time point, micro-CT, histology and immunohistochemistry analyses were performed. b Representative reconstructed 3D images of trabecular bone at injured sites. Scale bars: 500 μm. c Quantitative analysis of BMD, BV/TV, Tb.Th and Tb.N for trabecular bones at injured sites, n = 6. *p < 0.05, **p < 0.01, ***p < 0.001
Fig. 5 MSC-BMP2-Exos expedited bone regeneration through BMP2/Smad pathway. a 8-week-old male C57BL/6 mice were used for animal study. Holes with diameters of 1 mm were created at lateral epicondyle of right distal femur. At each time point, micro-CT, histology and immunohistochemistry analyses were performed. b Representative reconstructed 3D images of trabecular bone at injured sites. Scale bars: 500 μm. c Quantitative analysis of BMD, BV/TV, Tb.Th and Tb.N for trabecular bones at injured sites, n = 6. *p < 0.05, **p < 0.01, ***p < 0.001CC BY · PubMed Central
Fig. 6 Immunohistochemical analysis of BMP2/Smad pathway. a Radiographic images and H&E staining of mice distal femur. The injured areas are highlighted in red or black dotted lines. Scale bars: 200 μm. b Immunohistochemical staining of Smad1/5/8 marker at injured sites of trabecular bone. Red arrows indicate Smad1/5/8 positive cells. Scale bar: 20 μm
Fig. 6 Immunohistochemical analysis of BMP2/Smad pathway. a Radiographic images and H&E staining of mice distal femur. The injured areas are highlighted in red or black dotted lines. Scale bars: 200 μm. b Immunohistochemical staining of Smad1/5/8 marker at injured sites of trabecular bone. Red arrows indicate Smad1/5/8 positive cells. Scale bar: 20 μmCC BY · PubMed Central
Fig. 7 MSC-BMP2-Exos expedited cortical bone regeneration. a Holes with diameters of 1 mm were created at mid-diaphysis of femora. Micro-CT was performed on day 15 and day 30. b, c Representative reconstructed 3D images of cortical bone at injured sites. The injured areas are highlighted by yellow color. Scale bars: 500 μm. d Quantitative analysis of BV/TV and Cr.Th for cortical bones at injured sites, n = 5. *p < 0.05, **p < 0.01, ***p < 0.001
Fig. 7 MSC-BMP2-Exos expedited cortical bone regeneration. a Holes with diameters of 1 mm were created at mid-diaphysis of femora. Micro-CT was performed on day 15 and day 30. b, c Representative reconstructed 3D images of cortical bone at injured sites. The injured areas are highlighted by yellow color. Scale bars: 500 μm. d Quantitative analysis of BV/TV and Cr.Th for cortical bones at injured sites, n = 5. *p < 0.05, **p < 0.01, ***p < 0.001CC BY · PubMed Central
Fig. 8 In vivo retention and distribution of exosomes after local and systemic injection. a Nude mice with bone defects on right distal femurs were created. (i) For exosomes retention, Cy5.5 labelled exosomes were treated by local injection on both sides, and the retention of exosomes was imaged by IVIS Imaging System at 6, 24 and 48 h. (ii) For exosome distribution, Cy5.5 labelled exosomes were treated by intravenously injected through the tail vein, and distribution of exosomes in different organs was imaged at 48 h. b, c The retention of exosomes was imaged after local injection and performed quantitative analysis of fluorescent intensities at injection sites, n = 3. d, e Femurs and tibias of both sides in MSC-BMP2-Exo and MSC-Exo groups were excised at 48 h after exosome injection visualized by biofluorescence imaging, and performed quantitative analysis of fluorescent intensities at injection sites, n = 3. f, g Biodistribution of Cy5.5 labelled MSC-BMP2-Exo in major organs (heart, liver, spleen, lung, kidney, and femur) was visualized at 48 h after intravenously injection, and performed quantitative analysis of fluorescent intensities, n = 3. Bone defect was made on right distal femurs, and mice without bone defect was compared. *p < 0.05, **p < 0.01, ***p < 0.001
Fig. 8 In vivo retention and distribution of exosomes after local and systemic injection. a Nude mice with bone defects on right distal femurs were created. (i) For exosomes retention, Cy5.5 labelled exosomes were treated by local injection on both sides, and the retention of exosomes was imaged by IVIS Imaging System at 6, 24 and 48 h. (ii) For exosome distribution, Cy5.5 labelled exosomes were treated by intravenously injected through the tail vein, and distribution of exosomes in different organs was imaged at 48 h. b, c The retention of exosomes was imaged after local injection and performed quantitative analysis of fluorescent intensities at injection sites, n = 3. d, e Femurs and tibias of both sides in MSC-BMP2-Exo and MSC-Exo groups were excised at 48 h after exosome injection visualized by biofluorescence imaging, and performed quantitative analysis of fluorescent intensities at injection sites, n = 3. f, g Biodistribution of Cy5.5 labelled MSC-BMP2-Exo in major organs (heart, liver, spleen, lung, kidney, and femur) was visualized at 48 h after intravenously injection, and performed quantitative analysis of fluorescent intensities, n = 3. Bone defect was made on right distal femurs, and mice without bone defect was compared. *p < 0.05, **p < 0.01, ***p < 0.001CC BY · PubMed Central
Fig. 9 Plasmid DNAs could be packaged by stem cells and transported to recipient cells through exosomes. a Plasmid DNAs were labeled with POPO-3 (POPO-pDNA), and observed in donor hMSCs, secreted exosomes and recipient hMSCs. Exosomes were labeled with Dio green fluorescent dye. b Visualization of POPO-pDNA in hMSCs during liposome mediated transfection under fluorescent microscopy at 2, 6, 24, and 48 h. Scale bar: 200 μm. c Exosomes were collected from culture medium after transfection (PO-MSC-BMP2-Exo) and performed flow cytometry to analyze the amount of POPO-pDNA in exosomes. MSC-Exo was analyzed for baseline, and MSC-Exo containing free POPO-3 iodide was used as control (PO-MSC-Exo). Chloroquine was added in culture medium to inhibit lysosome dependent degradation (CQ-MSC-PO-BMP2-Exo). d Quantitative analysis of ratios of exosomes carrying POPO-pDNAs as determined by flow cytometry, n = 3. e PO-MSC-BMP2-Exo were then incubated with recipient hMSCs and observed by confocal microscopy. Exosomes were labelled by Dio (Green) and cell nucleus was stained by DAPI (Blue). Some exosomes carrying plasmid DNAs (exhibited yellow color) were found to accumulate around the nucleus (yellow arrows). Green arrow: exosomes, red arrow: plasmid DNA, yellow arrow: exosomes carrying plasmid DNA. Scale bar: 25 μm. **p < 0.01, ***p < 0.001
Fig. 9 Plasmid DNAs could be packaged by stem cells and transported to recipient cells through exosomes. a Plasmid DNAs were labeled with POPO-3 (POPO-pDNA), and observed in donor hMSCs, secreted exosomes and recipient hMSCs. Exosomes were labeled with Dio green fluorescent dye. b Visualization of POPO-pDNA in hMSCs during liposome mediated transfection under fluorescent microscopy at 2, 6, 24, and 48 h. Scale bar: 200 μm. c Exosomes were collected from culture medium after transfection (PO-MSC-BMP2-Exo) and performed flow cytometry to analyze the amount of POPO-pDNA in exosomes. MSC-Exo was analyzed for baseline, and MSC-Exo containing free POPO-3 iodide was used as control (PO-MSC-Exo). Chloroquine was added in culture medium to inhibit lysosome dependent degradation (CQ-MSC-PO-BMP2-Exo). d Quantitative analysis of ratios of exosomes carrying POPO-pDNAs as determined by flow cytometry, n = 3. e PO-MSC-BMP2-Exo were then incubated with recipient hMSCs and observed by confocal microscopy. Exosomes were labelled by Dio (Green) and cell nucleus was stained by DAPI (Blue). Some exosomes carrying plasmid DNAs (exhibited yellow color) were found to accumulate around the nucleus (yellow arrows). Green arrow: exosomes, red arrow: plasmid DNA, yellow arrow: exosomes carrying plasmid DNA. Scale bar: 25 μm. **p < 0.01, ***p < 0.001CC BY · PubMed Central
Fig. 10 Schematic illustration of exosomes derived from BMP2 genetically engineered MSCs promote bone regeneration. MSCs were genetically engineered by liposome mediated BMP2 gene delivery, and altered the content of secreted exosomes. This MSC-BMP2-Exo with the content derived from MSCs and up-regulated osteogenic related gene expression synergistically promoted bone regeneration. Both the liposome and exosomes rely on endosome-mediated cellular transportation, therefore, the pBMP2 delivered by liposome could be re-encapsulated in exosomes to present a safety carrier. This provide a strategy of making use of mediator cells as cellular factories to produce exosomes with designed therapeutic information
Fig. 10 Schematic illustration of exosomes derived from BMP2 genetically engineered MSCs promote bone regeneration. MSCs were genetically engineered by liposome mediated BMP2 gene delivery, and altered the content of secreted exosomes. This MSC-BMP2-Exo with the content derived from MSCs and up-regulated osteogenic related gene expression synergistically promoted bone regeneration. Both the liposome and exosomes rely on endosome-mediated cellular transportation, therefore, the pBMP2 delivered by liposome could be re-encapsulated in exosomes to present a safety carrier. This provide a strategy of making use of mediator cells as cellular factories to produce exosomes with designed therapeutic informationCC BY · PubMed Central

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Cited by

Sorted by citations

Metadata

Authors
Li, F., Wu, J., Li, D., Hao, L., Li, Y., Yi, D., Yeung, K. W. K., Chen, D., Lu, W. W., Pan, H., Wong, T. M., & Zhao, X.
Venue
Journal of Nanobiotechnology
Publisher
Springer Science and Business Media LLC
Published
2022-03-15
Volume
20
Issue
1
ISSN
1477-3155
DOI
10.1186/s12951-022-01347-3
PMC
PMC8922796
Cited by
99
References
10
Language
en
Licence
Funders
  • National Natural Science Foundation of China (81972071, 81802959)
  • Guangdong Basic and Applied Basic Research Foundation (2021A1515010191, 2018A030313888)
  • Science and Technology Research Funding of Shenzhen (JCYJ20210324102001003, JSGG20180507183242702, JCYJ20200109150420892)
  • HKU-SZH Fund for Shenzhen Key Medical Discipline (SZXK2020084)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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