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IPSC-derived MSC therapy induces immune tolerance and supports long-term graft survival in mouse orthotopic tracheal transplants.


ABSTRACT: BACKGROUND:Lung transplantation is a life-saving surgical replacement of diseased lungs in patients with end-stage respiratory malfunctions. Despite remarkable short-term recovery, long-term lung survival continues to face several major challenges, including chronic rejection and severe toxic side effects due to global immunosuppression. Stem cell-based immunotherapy has been recognized as a crucial immunoregulatory regimen in various preclinical and clinical studies. Despite initial therapeutic outcomes, conventional stem cells face key limitations. The novel Cymerus™ manufacturing facilitates production of a virtually limitless supply of consistent human induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells, which could play a key role in selective immunosuppression and graft repair during rejection. METHODS:Here, we demonstrated the impact of iPSC-derived human MSCs on the development of immune tolerance and long-term graft survival in mouse orthotopic airway allografts. BALB/c???C57BL/6 allografts were reconstituted with iPSC-derived MSCs (2 million/transplant/at d0), and allografts were examined for regulatory T cells (Tregs), oxygenation, microvascular blood flow, airway epithelium, and collagen deposition during rejection. RESULTS:We demonstrated that iPSC-derived MSC treatment leads to significant increases in hTSG-6 protein, followed by an upregulation of mouse Tregs and IL-5, IL-10, and IL-15 cytokines, which augments graft microvascular blood flow and oxygenation, and thereby maintained a healthy airway epithelium and prevented the subepithelial deposition of collagen at d90 post transplantation. CONCLUSIONS:Collectively, these data confirmed that iPSC-derived MSC-mediated immunosuppression has potential to establish immune tolerance and rescue allograft from sustained hypoxic/ischemic phase, and subsequently limits long-term airway epithelial injury and collagen progression, which therapeutically warrant a study of Cymerus iPSC-derived MSCs as a potential management option for immunosuppression in transplant recipients.

SUBMITTER: Khan MA 

PROVIDER: S-EPMC6757436 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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iPSC-derived MSC therapy induces immune tolerance and supports long-term graft survival in mouse orthotopic tracheal transplants.

Khan Mohammad Afzal MA   Alanazi Fatimah F   Ahmed Hala Abdalrahman HA   Shamma Talal T   Kelly Kilian K   Hammad Mohamed A MA   Alawad Abdullah O AO   Assiri Abdullah Mohammed AM   Broering Dieter Clemens DC  

Stem cell research & therapy 20190923 1


<h4>Background</h4>Lung transplantation is a life-saving surgical replacement of diseased lungs in patients with end-stage respiratory malfunctions. Despite remarkable short-term recovery, long-term lung survival continues to face several major challenges, including chronic rejection and severe toxic side effects due to global immunosuppression. Stem cell-based immunotherapy has been recognized as a crucial immunoregulatory regimen in various preclinical and clinical studies. Despite initial the  ...[more]

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