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MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs.

ABSTRACT: Mesenchymal stem or stromal cells (MSCs) have many potential therapeutic applications including therapies for cancers and tissue damages caused by cancers or radical cancer treatments. However, tissue-derived MSCs such as bone marrow MSCs (BM-MSCs) may promote cancer progression and have considerable donor variations and limited expandability. These issues hinder the potential applications of MSCs, especially those in cancer patients. To circumvent these issues, we derived MSCs from transgene-free human induced pluripotent stem cells (iPSCs) efficiently with a modified protocol that eliminated the need of flow cytometric sorting. Our iPSC-derived MSCs were readily expandable, but still underwent senescence after prolonged culture and did not form teratomas. These iPSC-derived MSCs homed to cancers with efficiencies similar to BM-MSCs but were much less prone than BM-MSCs to promote the epithelial-mesenchymal transition, invasion, stemness, and growth of cancer cells. The observations were probably explained by the much lower expression of receptors for interleukin-1 and TGF?, downstream protumor factors, and hyaluronan and its cofactor TSG6, which all contribute to the protumor effects of BM-MSCs. The data suggest that iPSC-derived MSCs prepared with the modified protocol are a safer and better alternative to BM-MSCs for therapeutic applications in cancer patients. The protocol is scalable and can be used to prepare the large number of cells required for "off-the-shelf" therapies and bioengineering applications.

SUBMITTER: Zhao Q

PROVIDER: S-EPMC4299223 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs.

Zhao Qingguo Q Gregory Carl A CA Lee Ryang Hwa RH Reger Roxanne L RL Qin Lizheng L Hai Bo B Park Min Sung MS Yoon Nara N Clough Bret B McNeill Eoin E Prockop Darwin J DJ Liu Fei F

Proceedings of the National Academy of Sciences of the United States of America 20141229 2

Mesenchymal stem or stromal cells (MSCs) have many potential therapeutic applications including therapies for cancers and tissue damages caused by cancers or radical cancer treatments. However, tissue-derived MSCs such as bone marrow MSCs (BM-MSCs) may promote cancer progression and have considerable donor variations and limited expandability. These issues hinder the potential applications of MSCs, especially those in cancer patients. To circumvent these issues, we derived MSCs from transgene-fr ...[more]

PMID: 25548183

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Project description:Background: Thin endometrial tissue is a leading cause of embryo transfer failure, potentially contributing to sustained infertility and associated adverse outcomes. The application of exosomes derived from autologous or allogeneic bone marrow-derived stem cells (BMSCs) has been used to promote uterine repair following injury, and there is also prior evidence that stem cell transplantation can bolster fertility. Genetic modifications represent a primary approach to enhancing exosomal therapy strategies. The present study thus explored the effects of Cardiotrophin-1 (CTF1)-modified BMSCs-exo on fertility-related outcomes. Methods: An adenoviral vector was used to generate CTF1-overexpressing BMSCs (C-BMSCs), after which exosomes were isolated from control BMSCs (BMSC-exos) and C-BMSCs (C-BMSC-exos). The angiogenic effects of C-BMSC-exo treatment were assessed through analyses of endothelial cell proliferation and tube formation. Model rats exhibiting endometrial thinning were administered C-BMSCs-exo, after which the effects of such treatment were assessed through H&E staining, Masson's trichrome staining, and immunofluorescence analyses. The mechanistic basis for the proangiogenic effects of CTF1 as a driver of endometrial regeneration was additionally explored. Results: C-BMSC-exo treatment of HUVECs was associated with enhanced neovascularization, as evidenced by improved in vitro proliferation, migration, and tube formation. Importantly, such treatment was also linked to tissue regeneration, neovascularization, and the suppression of localized tissue fibrosis in vivo. Regenerated endometrial tissue exhibited higher embryo receptivity and was associated with higher birth rates in treated rats. The upregulation of the JAK/PI3K/mTOR/STAT3 signaling pathways in C-BMSC-exo-treated rats may underscore the mechanistic basis whereby CTF1 can positively impact endometrial angiogenesis and regeneration. Conclusion: Our data suggest that exosomes produced by CTF1-modified BMSCs can more effectively promote the regeneration of endometrial and myometrial tissues, driving neovascularization in a manner that improves endometrial receptivity in a rat model system, highlighting the therapeutic promise of this approach for patients diagnosed with endometrial thinning.

Dataset Information

MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs.

Publications

MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs.

Similar Datasets

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