Non-clinical assessment of safety, biodistribution and tumorigenicity of human mesenchymal stromal cells

Thäte, Claudia; Woischwill, Christiane; Brandenburg, Gunda; Müller, Matthias J.; Böhm, Sonja; Baumgart, Joachim

doi:10.1016/j.toxrep.2021.11.016

Cited by 9 publications

(8 citation statements)

References 30 publications

(38 reference statements)

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“…No Alu DNA was detected in most tissues at the 4 weeks post-administration. 49 These results were consistent with those found with respect to Alu DNA detection in the lung up to 3 days post-inoculation in this study. Moreover, there was no Alu DNA detection in all tested tissues except the injection site (tail) 7 days post-administration.…”

Section: Discussionsupporting

confidence: 93%

“…Our results are consistent with the previous study, which reported no tumorigenicity after inoculating BALB/c-nude mice with umbilical cord bloodderived MSCs. 48 Thäte et al 49 also reported that no MSCinduced tumors in immunodeficient NSG mice after repeat-dose I.V. injections at 4 × 10 7 cells/kg after a follow-up of 6 months, which was similar to data in this study.…”

Section: Sexsupporting

confidence: 90%

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Preclinical Evaluation of interferon-gamma primed human Wharton’s jelly-derived mesenchymal stem cells

et al. 2023

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The potential of human mesenchymal stem cells (MSCs) for cell therapy has been investigated in numerous immune-mediated conditions; MSCs are considered one of the most promising cellular therapeutics to treat intractable diseases. Recently, approaches to prime MSCs have been investigated, thereby generating cellular products with enhanced potential for a variety of clinical applications. Interferon-gamma (IFN-γ) priming is a current approach used to increase the therapeutic efficacy of MSCs. In this study, we determined the systemic toxicity, tumorigenicity and biodistribution of IFN-γ-primed Wharton’s jelly-derived (WJ)-MSCs in male and female BALB/c-nu/nu mice. There were no deaths or pathologic lesions in the mice treated with 5 × 106 cells/kg IFN-γ-primed MSCs in the repeated dose study. In the tumorigenicity study, one of the subcutaneously treated mice showed bronchioloalveolar adenoma in the lung but tested negative for human-specific anti-mitochondrial antibody, suggesting the spontaneous murine origin of the adenoma. A biodistribution study using real-time quantitative polymerase chain reaction demonstrated the systemic IFN-γ-primed MSC clearance by day 28. Based on the toxicity, biodistribution, and tumorigenicity studies, we concluded that IFN-γ-primed MSCs at 5 × 106 cells/kg do not induce tumor formation and adverse changes.

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Section: Discussionsupporting

confidence: 93%

Section: Sexsupporting

confidence: 90%

Preclinical Evaluation of interferon-gamma primed human Wharton’s jelly-derived mesenchymal stem cells

et al. 2023

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“…This result implies the safety and tolerability of MSC, which is in line with the recent studies using MSCs in animal models. 18,19 The therapeutic dose of BM-MSCs was conservatively set at a low dose (2.50×10 4 cells/head in mice, ∼1.25×10 6 cells/kg in humans) because damaged tissues with embolism and demyelination were observed in the medium-dose group (1.25×10 5 cells/head in mice, ∼6.25×10 6 cells/kg in humans). We also identified the biodistribution of BM-MSCs in a mouse model to evaluate the in vivo persistence of BM-MSCs in major organs.…”

Section: Discussionmentioning

confidence: 99%

Safety and tolerability of bone marrow–derived mesenchymal stem cells in lupus animal models and a phase I clinical trial in humans

Chun

Choi

Kim

et al. 2022

Lupus

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Objective Several clinical trials aimed at treating various autoimmune diseases, including systemic lupus erythematosus (SLE), by introducing mesenchymal stem cells (MSCs) have been conducted. However, with refractory lupus nephritis (LN), the outcomes of MSC transplantation are not well known, and further validation is required. In particular, data concerning the safety and efficacy of LN treatment using bone marrow-derived MSCs (BM-MSCs) are still lacking. Methods We identified characteristics of BM-MSCs in terms of cell morphology, chromosomal stability, differentiation capacity, and phenotype through cell passages. The in vivo stability of BM-MSCs was evaluated by single-dose and repeated-dose toxicity tests, tumorigenicity tests, and biodistribution tests using lupus mouse models. Based on the encouraging nonclinical results, we conducted a nonrandomized, open-label, single-arm phase I clinical trial to evaluate the tolerability and safety of a single administration of haploidentical allogeneic BM-MSCs (CS20AT04) in seven LN patients (NCT03174587). We used a classical three + three design to find the optimal dosage. The starting dose was 2.0×106 cells/kg and escalated to 3.0×106 cells/kg if there was no dose-limiting toxicity (DLT). Evaluation of the safety and tolerability was assessed 28 days after the infusion, and the maximum tolerated dose was determined. Results Properly cultured BM-MSCs showed high proliferation and multipotency, but chromosomal changes were not found. There were two deaths by a rapid administration rate in the high-dose group (2.0×106 cells/head) in a single administration test. BM-MSCs were distributed in the kidneys until Day 7. In the phase I clinical trial, seven LN patients were enrolled. Participants received BM-MSCs through intravenous infusion. There was no DLT at both initial dose (2.0×106 cells/kg) and escalated dose (3.0×106 cells/kg). One patient was not administered the full 2.0×106 cells/kg dose because of a technical error during infusion. This patient did not show DLT. Three adverse events were reported, namely, one diarrhea, one toothache, and one arthralgia, and all were considered NCI-CTC grade I events. Conclusion We defined the characteristics of BM-MSCs and identified their safety and tolerability in both animal models and a phase I clinical trial. The maximum tolerated dose was determined to be 3.0×106 cells/kg in patients with LN.

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“…Immunodeficient mice are an increasingly popular research model due to their utility in studying human immune responses and cancer, and their use has increased significantly in preclinical research for multiple applications. 5,11,21,24,35,39,45,52 In preclinical studies in areas such as oncology and immunology, immunodeficient mice have been important to the understanding of mechanisms of disease, target identification and validation, and toxicologic effects of compounds. In addition, immunodeficient strains may recapitulate some of the immune dysfunction observed following immunosuppressive conditions in humans, such as chemotherapy, radiation therapy, surgery, infectious disease, or paraneoplastic syndromes, 17,48 and therefore may serve as a better predictor of toxicokinetics and safety in these instances.…”

Section: Introductionmentioning

confidence: 99%

“…33 In preclinical research, NSG mice have been used to test vaccine safety in the context of immunodeficient patients and the toxicity of human cell-based therapies. 24,45 Based on these research applications, NSG mice and other polygenic variants will likely continue to increase in popularity and value. However, immunodeficient mice created with multiple genetic mutations, including NSG mice, are very expensive to procure and often engrafted with tumors directly harvested from human patients and therefore irreplaceable.…”

Section: Introductionmentioning

confidence: 99%

Next-Generation Sequencing-Based Identification of Enterobacter hormaechei as Causative Agent of High Mortality Disease in NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ (NSG) Mice

Si,

Nickerson,

Simmons

et al. 2024

Toxicol Pathol

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NOD.Cg- Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice, lacking many components of a mature immune system, are at increased risk of disease. General understanding of potential pathogens of these mice is limited. We describe a high mortality disease outbreak caused by an opportunistic bacterial infection in NSG mice. Affected animals exhibited perianal fecal staining, dehydration, and wasting. Histopathologic lesions included a primary necrotizing enterocolitis, with inflammatory and necrotizing lesions also occurring in the liver, kidneys, heart, and brain of some mice. All affected individuals tested negative for known opportunistic pathogens of immunodeficient mice. We initially identified a member of Enterobacter cloacae complex (ECC) in association with the outbreak by traditional diagnostics. ECC was cultured from extraintestinal organs, both with and without histopathologic lesions, suggesting bacteremia. Infrared spectroscopy and MALDI-TOF mass spectrometry demonstrated that isolates from the outbreak shared molecular features and likely a common origin. We subsequently hypothesized that advanced sequencing methods would identify a single species of ECC associated with clinical disease. Using a novel targeted amplicon-based next-generation sequencing assay, we identified Enterobacter hormaechei in association with this outbreak. Knowledge of this organism as a potential opportunistic pathogen in NSG mice is critical for preclinical studies to prevent loss of animals and confounding of research.

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Non-clinical assessment of safety, biodistribution and tumorigenicity of human mesenchymal stromal cells

Abstract: Graphical abstract

Cited by 9 publications

References 30 publications

Preclinical Evaluation of interferon-gamma primed human Wharton’s jelly-derived mesenchymal stem cells

Preclinical Evaluation of interferon-gamma primed human Wharton’s jelly-derived mesenchymal stem cells

Safety and tolerability of bone marrow–derived mesenchymal stem cells in lupus animal models and a phase I clinical trial in humans

Next-Generation Sequencing-Based Identification of Enterobacter hormaechei as Causative Agent of High Mortality Disease in NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ (NSG) Mice

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Non-clinical assessment of safety, biodistribution and tumorigenicity of human mesenchymal stromal cells

Abstract: Graphical abstract

Cited by 9 publications

References 30 publications

Preclinical Evaluation of interferon-gamma primed human Wharton’s jelly-derived mesenchymal stem cells

Preclinical Evaluation of interferon-gamma primed human Wharton’s jelly-derived mesenchymal stem cells

Safety and tolerability of bone marrow–derived mesenchymal stem cells in lupus animal models and a phase I clinical trial in humans

Next-Generation Sequencing-Based Identification of Enterobacter hormaechei as Causative Agent of High Mortality Disease in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) Mice

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Next-Generation Sequencing-Based Identification of Enterobacter hormaechei as Causative Agent of High Mortality Disease in NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ (NSG) Mice