Production, safety and efficacy of iPSC-derived mesenchymal stromal cells in acute steroid-resistant graft versus host disease: a phase I, multicenter, open-label, dose-escalation study

Bloor, Adrian; Patel, Amit; Griffin, James E.; Gilleece, Maria; Radia, Rohini; Yeung, David T.; Drier, Diana; Larson, Laurie S.; Uenishi, Gene I.; Hei, Derek J.; Kelly, Kilian; Slukvin, Igor I.; Rasko, John E.J.

doi:10.1038/s41591-020-1050-x

Cited by 206 publications

(172 citation statements)

References 43 publications

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“…MSCs can be also derived from induced pluripotent stem cells (iPSCs). It has been demonstrated that human iPSC-derived MSCs (iPSC-MSCs) possess higher proliferative and immunomodulatory potentials (Zhang et al, 2012;Bloor et al, 2020). Besides, due to the higher expression of TNFαIP2, iPSC-MSCs are more responsive to TNFα-induced tunneling nanotube formation for mitochondrial transfer and have been shown to be more protective against cardiomyocyte damage (Zhang et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

TNFR2 Is a Crucial Hub Controlling Mesenchymal Stem Cell Biological and Functional Properties

Beldi

Bahiraii

Lezin

et al. 2020

Front. Cell Dev. Biol.

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Mesenchymal stem cells (MSCs) have drawn lots of attention as gold standard stem cells in fundamental and clinical researches during the last 20 years. Due to their tissue and vascular repair capacities, MSCs have been used to treat a variety of degenerative disorders. Moreover, MSCs are able to modulate immune cells’ functions, particularly T cells while inducing regulatory T cells (iTregs). MSCs are very sensitive to inflammatory signals. Their biological functions could remarkably vary after exposure to different pro-inflammatory cytokines, notably TNFα. In this article, we have explored the importance of TNFR2 expression in a series of MSCs’ biological and functional properties. Thus, MSCs from wild-type (WT) and TNFR2 knockout (TNFR2 KO) mice were isolated and underwent several ex vivo experiments to investigate the biological significance of TNFR2 molecule in MSC main functions. Hampering in TNFR2 signaling resulted in reduced MSC colony-forming units and proliferation rate and diminished the expression of all MSC characteristic markers such as stem cell antigen-1 (Sca1), CD90, CD105, CD44, and CD73. TNFR2 KO-MSCs produced more pro-inflammatory cytokines like TNFα, IFNγ, and IL-6 and less anti-inflammatory mediators such as IL-10, TGFβ, and NO and induced Tregs with less suppressive effect. Furthermore, the TNFR2 blockade remarkably decreased MSC regenerative functions such as wound healing, complex tube formation, and endothelial pro-angiogenic support. Therefore, our results reveal the TNFα–TNFR2 axis as a crucial regulator of MSC immunological and regenerative functions.

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Section: Discussionmentioning

confidence: 99%

TNFR2 Is a Crucial Hub Controlling Mesenchymal Stem Cell Biological and Functional Properties

Beldi

Bahiraii

Lezin

et al. 2020

Front. Cell Dev. Biol.

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“…46 GMP-grade MSCs derived from PSCs were recently used for clinical trials to treat the refractory graft-versus-host-disease. 47 TCs-MSCs cotransplantation may provide another therapeutic scheme to overcome many limitations of MSCs. Another challenge is to select lung TCs-specific biomarkers to differ from other cell types.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of interactions between lung‐origin telocytes and mesenchymal stem cells to treat experimental acute lung injury

Zhang

Song

Shi

et al. 2020

Clinical & Translational Med

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“…Indeed, human iPSC-MSCs may represent a better option to overcome these limitations and be more indicated for tissue regeneration [ 95 ]. iPSC-MSCs may therefore represent an unlimited cell source for the production of EVs in large scale [ 96 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of Stem Cell-Derived Extracellular Vesicles on Damaged Human Corneal Endothelial Cells

Nuzzi

Buono

Scalabrin

et al. 2021

Stem Cells International

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Purpose. Human corneal endothelial cells (HCECs) are essential to visual function; however, since they have limited proliferative capacity in vivo, they are prone to corneal endothelial dysfunction. At present, the only treatment is a corneal transplantation from donor cadavers. Also, due to a global shortage of donor corneas, it is important to find alternative strategies. Recent studies highlight that stem cell–derived extracellular vesicles (EVs) play a relevant role in stem cell-induced regeneration by reprogramming injured cells and inducing proregenerative pathways. The aim of this work is to evaluate whether EVs derived from mesenchymal stem cells (MSC-EVs) are able to promote regeneration of damaged HCECs. Methods. We isolated HCECs from discarded corneas in patients undergoing corneal transplantation or enucleation ( N = 23 patients). Bone marrow mesenchymal stem cells (MSCs) were obtained from Lonza, cultured, and characterized. MSC-EVs were obtained from supernatants of MSCs. In order to establish a valid in vitro damage model to test the regenerative potential of EVs on HCECs, we evaluated the proliferation rate and the apoptosis after exposing the cells to serum-deprived medium at different concentrations for 24 hours. We then evaluated the HCEC migration through a wound healing assay. Results. In the selected serum deprivation damage conditions, the treatment with different doses of MSC-EVs resulted in a significantly higher proliferation rate of HCECs at all the tested concentrations of EVs ( 5 ‐ 20 × 10 3 MSC-EV/cell). MSC-EVs/cell induced a significant decrease in number of total apoptotic cells after 24 hours of serum deprivation. Finally, the wound healing assay showed a significantly faster repair of the wound after HCEC treatment with MSC-EVs. Conclusions. Results highlight the already well-known proregenerative potential of MSC-EVs in a totally new biological model, the endothelium of the cornea. MSC-EVs, indeed, induced proliferation and survival of HCECs, promoting the migration of HCECs in vitro.

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Production, safety and efficacy of iPSC-derived mesenchymal stromal cells in acute steroid-resistant graft versus host disease: a phase I, multicenter, open-label, dose-escalation study

Cited by 206 publications

References 43 publications

TNFR2 Is a Crucial Hub Controlling Mesenchymal Stem Cell Biological and Functional Properties

TNFR2 Is a Crucial Hub Controlling Mesenchymal Stem Cell Biological and Functional Properties

Mechanisms of interactions between lung‐origin telocytes and mesenchymal stem cells to treat experimental acute lung injury

Effect of Stem Cell-Derived Extracellular Vesicles on Damaged Human Corneal Endothelial Cells

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