Human mesenchymal stromal cells undergo apoptosis and fragmentation after intravenous application in immune-competent mice

Leibacher, Johannes; Dauber, Katrin; Ehser, Sabrina; Brixner, V.; Kollár, K; Vogel, Anja; Spohn, Gabi; Schäfer, Richard; Seifried, Erhard; Henschler, Reinhard

doi:10.1016/j.jcyt.2016.09.010

Cited by 43 publications

(44 citation statements)

References 37 publications

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“…In immunocompetent (C57BL/6) mice intravenously injected with human bone marrow-derived MSCs, qPCR revealed a rapid loss of traceable human DNA within the first 24 h after injection. At that time point, only <0.1% of the initially injected cells were detectable in the lungs (maximum: 52.5% at 5 min), and human cells were undetectable in the liver (maximum: 0.05% at 2 h) [23]. Immunodeficiency, as was the case in the present study, seems to have a favoring effect on persistence of exogenous cells, which, however, would not be given in non-immuno-suppressed human patients.…”

Section: Discussionmentioning

confidence: 99%

In vivo safety profile and biodistribution of GMP-manufactured human skin-derived ABCB5-positive mesenchymal stromal cells for use in clinical trials

Tappenbeck

Schröder²,

Niebergall-Roth³

et al. 2019

Cytotherapy

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Background aims. Human dermal ABCB5-expressing mesenchymal stromal cells (ABCB5 + MSCs) represent a promising candidate for stem cell based therapy of various currently uncurable diseases in several fields of regenerative medicine. We have developed and validated a method to isolate, from human skin samples, and expand ABCB5 + MSCs that meet the guideline criteria of the International Society for Cellular Therapy. We are able to process these cells into a Good Manufacturing Practice conforming, MSC-based advanced-therapy medicinal product. Methods. To support the development of ABCB5 + MSCs for potential therapeutic topical, intramuscular and intravenous administration, we have tested our product in a series of Good Laboratory Practice compliant nonclinical in-vivo studies addressing all relevant aspects of biosafety, including potential long-term persistence and proliferation, distribution to nontarget tissues, differentiation into undesired cell types, ectopic tissue formation, tumor formation and local tissue reaction. Results. (i) Subcutaneous application of 1 × 10 7 ABCB5 + MSCs/animal and intravenous application of 2 × 10 6 ABCB5 + MSCs/animal, respectively, to immunocompromised mice did not result in safety-relevant biodistribution, persistence or proliferation of the cells; (ii) three monthly subcutaneous injections of ABCB5 + MSCs at doses ranging from 1 × 10 5 to 1 × 10 7 cells/animal and three biweekly intravenous injections of 2 × 10 6 ABCB5 + MSCs/animal, respectively, to immunocompromised mice were nontoxic and revealed no tumorigenic potential; and (iii) intramuscular injection of 5 × 10 6 ABCB5 + MSCs/animal to immunocompromised mice was locally well tolerated. Discussion. The present preclinical in vivo data demonstrate the local and systemic safety and tolerability of a novel advanced-therapy medicinal product based on human skin-derived ABCB5 + MSCs.

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Section: Discussionmentioning

confidence: 99%

In vivo safety profile and biodistribution of GMP-manufactured human skin-derived ABCB5-positive mesenchymal stromal cells for use in clinical trials

Tappenbeck

Schröder²,

Niebergall-Roth³

et al. 2019

Cytotherapy

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“…1e), while MSCs treated with 0.5 µM Staurosporine (STS; #ab120056; Abcam Co. Ltd., MA, USA) for 36 h were used as a reference ( Fig. 1f) [17]. After pressurization, all of the medium (including cells) in each bag was aspirated and then transferred to 50-ml conical tubes (Falcon, Corning Inc.).…”

Section: Inducing Apoptosis Of Mscs and Collection Techniquementioning

confidence: 99%

Ex vivo Induction of Apoptotic Mesenchymal Stem Cell by High Hydrostatic Pressure

Morimoto

et al. 2020

Stem Cell Rev and Rep

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Among promising solutions for tissue repair and wound healing, mesenchymal stem (or stromal) cells (MSCs) have been a focus of attention and have become the most clinically studied experimental cell therapy. Recent studies reported the importance of apoptosis in MSC-mediated immunomodulation, in which apoptotic MSCs (apoMSCs) were shown to be superior to living MSCs. Nowadays, high hydrostatic pressure (HHP), a physical technique that uses only fluid pressure, has been developed and applied in various bioscience fields, including biotechnology, biomaterials, and regenerative medicine, as its safe and simply operation. In the current study, we investigated the impact of HHP treatment on human bone marrow-MSC survival and proliferation. Based on the detection of executioner caspase activation, phosphatidylserine exposure, DNA fragmentation (TUNEL) and irrefutable ultrastructural morphological changes on transmission electron microscopy (TEM), our data revealed that HHP treatment induced complete apoptosis in MSCs. Notably, this technique might provide manipulated products for use in cell-based therapies as manufacturing capability expands. We hope that our findings will contribute to the improvement of MSCs or EVs in translational research development.

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“…Moreover, small vessel entrapment of systemically delivered stem cells reduces their viability, leading to their fragmentation after intravenous (i.v.) infusion [10] , [11] , [12] . Therefore, it is reasonable to assume that the homing capacity of the transplanted stem cells is essential for their therapeutic efficacy, and targeting stem cell delivery is required for dose finding and a prerequisite to unfold their full therapeutic potential.…”

Section: Introductionmentioning

confidence: 99%

Modulating endothelial adhesion and migration impacts stem cell therapies efficacy

Schäfer

Schwab

Siegel³

et al. 2020

EBioMedicine

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Background Limited knowledge of stem cell therapies` mechanisms of action hampers their sustainable implementation into the clinic. Specifically, the interactions of transplanted stem cells with the host vasculature and its implications for their therapeutic efficacy are not elucidated. We tested whether adhesion receptors and chemokine receptors on stem cells can be functionally modulated, and consequently if such modulation may substantially affect therapeutically relevant stem cell interactions with the host endothelium. Methods We investigated the effects of cationic molecule polyethylenimine (PEI) treatment with or without nanoparticles on the functions of adhesion receptors and chemokine receptors of human bone marrow-derived Mesenchymal Stem Cells (MSC). Analyses included MSC functions in vitro, as well as homing and therapeutic efficacy in rodent models of central nervous system´s pathologies in vivo. Findings PEI treatment did not affect viability, immunomodulation or differentiation potential of MSC, but increased the CCR4 expression and functionally blocked their adhesion receptors, thus decreasing their adhesion capacity in vitro. Intravenously applied in a rat model of brain injury, the homing rate of PEI-MSC in the brain was highly increased with decreased numbers of adherent PEI-MSC in the lung vasculature. Moreover, in comparison to untreated MSC, PEI-MSC featured increased tumour directed migration in a mouse glioblastoma model, and superior therapeutic efficacy in a murine model of stroke. Interpretation Balanced stem cell adhesion and migration in different parts of the vasculature and tissues together with the local microenvironment impacts their therapeutic efficacy. Funding Robert Bosch Stiftung, IZEPHA grant, EU grant 7 FP Health

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Human mesenchymal stromal cells undergo apoptosis and fragmentation after intravenous application in immune-competent mice

Cited by 43 publications

References 37 publications

In vivo safety profile and biodistribution of GMP-manufactured human skin-derived ABCB5-positive mesenchymal stromal cells for use in clinical trials

In vivo safety profile and biodistribution of GMP-manufactured human skin-derived ABCB5-positive mesenchymal stromal cells for use in clinical trials

Ex vivo Induction of Apoptotic Mesenchymal Stem Cell by High Hydrostatic Pressure

Modulating endothelial adhesion and migration impacts stem cell therapies efficacy

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