Early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome-associated factor TSG-6
Abstract Background Mesenchymal stem cells (MSCs) are promising tools for the treatment of human lung disease and other pathologies relevant to newborn medicine. Recent studies have established MSC exosomes (EXO), as one of the main therapeutic vectors of MSCs in mouse models of multifactorial chron...
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| Format: | Article |
| Language: | English |
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BMC
2018-06-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | http://link.springer.com/article/10.1186/s13287-018-0903-4 |
| _version_ | 1817978606608973824 |
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| author | Sushma Chaubey Sam Thueson Devasena Ponnalagu Mohammad Afaque Alam Ciprian P. Gheorghe Zubair Aghai Harpreet Singh Vineet Bhandari |
| author_facet | Sushma Chaubey Sam Thueson Devasena Ponnalagu Mohammad Afaque Alam Ciprian P. Gheorghe Zubair Aghai Harpreet Singh Vineet Bhandari |
| author_sort | Sushma Chaubey |
| collection | DOAJ |
| description | Abstract Background Mesenchymal stem cells (MSCs) are promising tools for the treatment of human lung disease and other pathologies relevant to newborn medicine. Recent studies have established MSC exosomes (EXO), as one of the main therapeutic vectors of MSCs in mouse models of multifactorial chronic lung disease of preterm infants, bronchopulmonary dysplasia (BPD). However, the mechanisms underlying MSC-EXO therapeutic action are not completely understood. Using a neonatal mouse model of human BPD, we evaluated the therapeutic efficiency of early gestational age (GA) human umbilical cord (hUC)-derived MSC EXO fraction and its exosomal factor, tumor necrosis factor alpha-stimulated gene-6 (TSG-6). Methods Conditioned media (CM) and EXO fractions were isolated from 25 and 30 weeks GA hUC-MSC cultures grown in serum-free media (SFM) for 24 h. Newborn mice were exposed to hyperoxia (> 95% oxygen) and were given intraperitoneal injections of MSC-CM or MSC-CM EXO fractions at postnatal (PN) day 2 and PN4. They were then returned to room air until PN14 (in a mouse model of severe BPD). The treatment regime was followed with (rh)TSG-6, TSG-6-neutralizing antibody (NAb), TSG-6 (si)RNA-transfected MSC-CM EXO and their appropriate controls. Echocardiography was done at PN14 followed by harvesting of lung, heart and brain for assessment of pathology parameters. Results Systemic administration of CM or EXO in the neonatal BPD mouse model resulted in robust improvement in lung, cardiac and brain pathology. Hyperoxia-exposed BPD mice exhibited pulmonary inflammation accompanied by alveolar-capillary leakage, increased chord length, and alveolar simplification, which was ameliorated by MSC CM/EXO treatment. Pulmonary hypertension and right ventricular hypertrophy was also corrected. Cell death in brain was decreased and the hypomyelination reversed. Importantly, we detected TSG-6, an immunomodulatory glycoprotein, in EXO. Administration of TSG-6 attenuated BPD and its associated pathologies, in lung, heart and brain. Knockdown of TSG-6 by NAb or by siRNA in EXO abrogated the therapeutic effects of EXO, suggesting TSG-6 as an important therapeutic molecule. Conclusions Preterm hUC-derived MSC-CM EXO alleviates hyperoxia-induced BPD and its associated pathologies, in part, via exosomal factor TSG-6. The work indicates early systemic intervention with TSG-6 as a robust option for cell-free therapy, particularly for treating BPD. |
| first_indexed | 2024-04-13T22:32:19Z |
| format | Article |
| id | doaj.art-6b1bfdf36c284ba9af1850ea7871cba3 |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-04-13T22:32:19Z |
| publishDate | 2018-06-01 |
| publisher | BMC |
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| series | Stem Cell Research & Therapy |
| spelling | doaj.art-6b1bfdf36c284ba9af1850ea7871cba32022-12-22T02:26:53ZengBMCStem Cell Research & Therapy1757-65122018-06-019112610.1186/s13287-018-0903-4Early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome-associated factor TSG-6Sushma Chaubey0Sam Thueson1Devasena Ponnalagu2Mohammad Afaque Alam3Ciprian P. Gheorghe4Zubair Aghai5Harpreet Singh6Vineet Bhandari7Section of Neonatal-Perinatal Medicine, Department of Pediatrics, Drexel University College of MedicineSection of Neonatal-Perinatal Medicine, Department of Pediatrics, Drexel University College of MedicineDepartment of Pharmacology & Physiology, Drexel University College of MedicineSection of Neonatal-Perinatal Medicine, Department of Pediatrics, Drexel University College of MedicineDepartment of Obstetrics and Gynecology, Loma Linda University School of MedicineDivison of Neonatology, Department of Pediatrics, Thomas Jefferson University HospitalDepartment of Pharmacology & Physiology, Drexel University College of MedicineSection of Neonatal-Perinatal Medicine, Department of Pediatrics, Drexel University College of MedicineAbstract Background Mesenchymal stem cells (MSCs) are promising tools for the treatment of human lung disease and other pathologies relevant to newborn medicine. Recent studies have established MSC exosomes (EXO), as one of the main therapeutic vectors of MSCs in mouse models of multifactorial chronic lung disease of preterm infants, bronchopulmonary dysplasia (BPD). However, the mechanisms underlying MSC-EXO therapeutic action are not completely understood. Using a neonatal mouse model of human BPD, we evaluated the therapeutic efficiency of early gestational age (GA) human umbilical cord (hUC)-derived MSC EXO fraction and its exosomal factor, tumor necrosis factor alpha-stimulated gene-6 (TSG-6). Methods Conditioned media (CM) and EXO fractions were isolated from 25 and 30 weeks GA hUC-MSC cultures grown in serum-free media (SFM) for 24 h. Newborn mice were exposed to hyperoxia (> 95% oxygen) and were given intraperitoneal injections of MSC-CM or MSC-CM EXO fractions at postnatal (PN) day 2 and PN4. They were then returned to room air until PN14 (in a mouse model of severe BPD). The treatment regime was followed with (rh)TSG-6, TSG-6-neutralizing antibody (NAb), TSG-6 (si)RNA-transfected MSC-CM EXO and their appropriate controls. Echocardiography was done at PN14 followed by harvesting of lung, heart and brain for assessment of pathology parameters. Results Systemic administration of CM or EXO in the neonatal BPD mouse model resulted in robust improvement in lung, cardiac and brain pathology. Hyperoxia-exposed BPD mice exhibited pulmonary inflammation accompanied by alveolar-capillary leakage, increased chord length, and alveolar simplification, which was ameliorated by MSC CM/EXO treatment. Pulmonary hypertension and right ventricular hypertrophy was also corrected. Cell death in brain was decreased and the hypomyelination reversed. Importantly, we detected TSG-6, an immunomodulatory glycoprotein, in EXO. Administration of TSG-6 attenuated BPD and its associated pathologies, in lung, heart and brain. Knockdown of TSG-6 by NAb or by siRNA in EXO abrogated the therapeutic effects of EXO, suggesting TSG-6 as an important therapeutic molecule. Conclusions Preterm hUC-derived MSC-CM EXO alleviates hyperoxia-induced BPD and its associated pathologies, in part, via exosomal factor TSG-6. The work indicates early systemic intervention with TSG-6 as a robust option for cell-free therapy, particularly for treating BPD.http://link.springer.com/article/10.1186/s13287-018-0903-4Bronchopulmonary dysplasiaMesenchymal stem cellsWharton’s jellySecretomeExosomesNewborn |
| spellingShingle | Sushma Chaubey Sam Thueson Devasena Ponnalagu Mohammad Afaque Alam Ciprian P. Gheorghe Zubair Aghai Harpreet Singh Vineet Bhandari Early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome-associated factor TSG-6 Stem Cell Research & Therapy Bronchopulmonary dysplasia Mesenchymal stem cells Wharton’s jelly Secretome Exosomes Newborn |
| title | Early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome-associated factor TSG-6 |
| title_full | Early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome-associated factor TSG-6 |
| title_fullStr | Early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome-associated factor TSG-6 |
| title_full_unstemmed | Early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome-associated factor TSG-6 |
| title_short | Early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome-associated factor TSG-6 |
| title_sort | early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome associated factor tsg 6 |
| topic | Bronchopulmonary dysplasia Mesenchymal stem cells Wharton’s jelly Secretome Exosomes Newborn |
| url | http://link.springer.com/article/10.1186/s13287-018-0903-4 |
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