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

ABSTRACT: 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?×?107 ABCB5+ MSCs/animal and intravenous application of 2?×?106 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?×?105 to 1?×?107 cells/animal and three biweekly intravenous injections of 2?×?106 ABCB5+ MSCs/animal, respectively, to immunocompromised mice were nontoxic and revealed no tumorigenic potential; and (iii) intramuscular injection of 5?×?106 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.

SUBMITTER: Tappenbeck N

PROVIDER: S-EPMC6513723 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Tappenbeck Nils N Schröder Hannes M HM Niebergall-Roth Elke E Hassinger Fathema F Dehio Ulf U Dieter Kathrin K Kraft Korinna K Kerstan Andreas A Esterlechner Jasmina J Frank Natasha Y NY Scharffetter-Kochanek Karin K Murphy George F GF Orgill Dennis P DP Beck Joachim J Frank Markus H MH Ganss Christoph C Kluth Mark A MA

Cytotherapy 20190314 5

<h4>Background aims</h4>Human dermal ABCB5-expressing mesenchymal stromal cells (ABCB5<sup>+</sup> 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<sup>+</sup> MSCs that meet the guideline criteria of the International Society for Cellular Therapy. We are able to process these cells into a Good Manufact ...[more]

PMID: 30878384

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Project description:BackgroundMesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are a promising cell-free therapy for acute lung injury (ALI). To date, no studies have investigated their biodistribution in ALI or discerned the timing of administration for maximal lung targeting, which are crucial considerations for clinical translation. Our study aimed to characterize a mouse model of ALI and establish the distribution kinetics and optimal timing of MSC-EV delivery during lung injury.MethodsMSC-EVs were isolated by ultracentrifugation alone (U/C) or tangential flow filtration with ultracentrifugation (TFF-U/C) and characterized by nanoparticle tracking analysis and western blot. A lipopolysaccharide (LPS)-induced mouse model of ALI was established to study the inflammatory response over 72 h. ALI was assessed by histological lung injury score, bronchoalveolar lavage fluid cell count and inflammatory cytokines. For biodistribution studies, ALI mice were intravenously administered fluorescently labeled MSC-EVs to determine the optimal timing of administration and organ-specific biodistribution. Live in vivo and ex vivo fluorescence imaging was conducted at various timepoints post-EV injection.ResultsEVs isolated by either ultracentrifugation alone or TFF-U/C displayed comparable size distribution (~ 50-350 nm) and EV marker expression (CD63/81). TFF-U/C generated a 5.4-fold higher particle concentration and 3.9-fold higher total protein when compared to ultracentrifugation alone. From the inflammatory time-course study, cell count and IL-1β peaked in bronchoalveolar lavage fluid at 24 h after ALI induction. MSC-EVs delivered at 24 h (as opposed to 0.5 h, 5 h or 10 h) after disease induction resulted in a 2.7-4.4-fold higher lung uptake of EVs. Biodistribution studies comparing organ-specific MSC-EV uptake showed progressive lung accumulation up to 48 h post-delivery (threefold higher than the spleen/liver), with a decline at 72 h. Importantly, lung EV fluorescence at 48 h in ALI mice was significantly elevated as compared to control mice. The lung tropism of MSC-EVs was further validated as therapeutically inert EVs derived from HEK293T cells accumulated mainly to the spleen and liver with a 5.5-fold lower distribution to the lungs as compared to MSC-EVs.ConclusionMSC-EVs exhibit maximal lung accumulation when administered during heightened inflammation at 24 h after ALI induction. This lung tropism suggests that MSC-EVs may serve as a practical rescue treatment for acute inflammatory respiratory conditions.

Dataset Information

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

Publications

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

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