Safety and biodistribution study of bone marrow–derived mesenchymal stromal cells and mononuclear cells and the impact of the administration route in an intact porcine model

Mäkelä, Tuomas; Takalo, Reijo; Arvola, Oiva; Haapanen, Henri; Yannopoulos, Fredrik; Blanco, Roberto; Ahvenjärvi, Lauri; Kiviluoma, Kai; Kerkelä, Erja; Nystedt, Johanna; Juvonen, Tatu; Lehenkari, Petri

doi:10.1016/j.jcyt.2014.12.004

Cited by 77 publications

(60 citation statements)

References 45 publications

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“…Therefore, obstructive events during lung passage are expected after MSC administration which is supported by their relatively high adhesion capacity and their tendency to aggregate, leading to clogging of capillaries [42, 45, 46]. Contrary to the observation of MSC retention in the lungs, one study analysing the biodistribution of BMSCs after IA injection found a decreased deposition in the lungs and increased uptake in other organs, especially in the liver [47]. With regard to engraftment time and rates, studies comparing both application routes have demonstrated a major association between IA application and the early and increased accumulation in therapeutic target tissues [14, 16].…”

Section: Discussionmentioning

confidence: 99%

The effect of adipose tissue-derived stem cells in a middle cerebral artery occlusion stroke model depends on their engraftment rate

et al. 2017

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BackgroundIn the field of experimental stem cell therapy, intra-arterial (IA) delivery yields the best results concerning, for example, migrated cell number at the targeted site. However, IA application also appears to be associated with increased mortality rates and infarction. Since many rodent studies systemically apply 1 × 106 cells, this could also be a consequence of engrafted cell number. The aim of this study was therefore to investigate the effect of different doses of adipose tissue-derived stem cells (ASCs) on engraftment rates and stroke outcome measured in vivo using 9.4-T high-field magnetic resonance imaging (MRI).MethodsMale Wistar rats (n = 43) underwent a middle cerebral artery occlusion (MCAo) for 45 or 90 min, followed by IA delivery of either saline or 1 × 106, 3 × 105, or 5 × 104 ASCs pre-labelled with very small superparamagnetic iron oxide particles (VSOPs). MRI (9.4-T) analysis was performed 48 h and 9 days post-MCAo. Lesion volumes were assessed by analysis of T2-weighted images and cell signal tracking showing cell engraftment and active cell migration by an improved T2*-analysis.ResultsThe ASC-derived signal intensity increased in the affected hemisphere 48 h post MCAo with injected cell number (p < 0.05). The analysis of stroke volumes revealed an increased infarction after injection of 1 × 106 ASCs compared to controls or application of 5 × 104 ASCs (p < 0.05). At 9 days post-MCAo, injection of 3 × 105 ASCs resulted in reduced infarct volumes (p < 0.05). Correspondingly, MRI analysis revealed no changes in cell numbers between both MRI examinations but showed active ASC migration to the site of infarction.ConclusionOur results confirm that IA injection is an efficient way of targeting damaged brain tissue but its usefulness strongly depends on the right dose of delivered stem cells since this factor has a strong influence on migration rate and infarct volume, with better results for doses below 1 × 106 cells. Future challenges will include the determination of therapeutic doses for best cellular engraftment and stroke outcome.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0545-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The effect of adipose tissue-derived stem cells in a middle cerebral artery occlusion stroke model depends on their engraftment rate

et al. 2017

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“…and intra-arterial (i.a.) routes was compared in pigs33. While both routes were found to be safe, pulmonary entrapment of MSC was observed only in the i.v.-administered animals.…”

Section: Discussionmentioning

confidence: 99%

Preclinical safety & toxicity evaluation of pooled, allogeneic human bone marrow-derived mesenchymal stromal cells

Rengasamy¹,

Gupta²,

Kolkundkar³

et al. 2016

Indian J Med Res

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Background & objectives:Administration of ex vivo-expanded human bone marrow-derived mesenchymal stromal cells (hBMMSC) obtained from single donors has shown therapeutic benefits in both preclinical and clinical studies. In this study, the safety, toxicity and biodistribution profiles of a pooled hBMMSC population, produced from three healthy donors were assessed in rodent and non-rodents.Methods:The pooled hBMMSC population was characterized by their expression of various cell surface markers, differentiation potential and immunomodulatory activity. To establish in vivo safety of the pooled cells, these were administered by various injection routes into rodents and non-rodents to determine overall toxicity, biodistribution and tumorigenic potential in a series of preclinical studies.Results:Single injections of hBMMSC at various doses through intravenous or intramuscular routes did not cause toxicity in rats and rabbits. In addition, repeat administration of hBMMSC was also well tolerated by rats, and no prenatal toxicity was observed by multiple administration in the same animal species. Ex vivo-expanded and cryopreserved hBMMSCs did not induce tumour formation in severe combined immunodeficient (SCID) mice.Interpretation & conclusions:Our results showed that the pooled hBMMSC population was non-toxic, non-teratogenic and non-tumorigenic in animals. Further studies need to be done to find out if it can be safely administered in human patients.

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“…One important mechanism was attenuation of allostimulatory dendritic cells [23]. After intravenous application, the largest fraction of MSCs were pooled in the lungs [57] and lymph nodes and did not reach the liver. Still, most studies in solid organ transplantation apply intravenous MSC infusion.…”

Section: Discussionmentioning

confidence: 99%

Safety and Tolerance of Donor-Derived Mesenchymal Stem Cells in Pediatric Living-Donor Liver Transplantation: The MYSTEP1 Study

Hartleif

Schumm

Döring

et al. 2017

Stem Cells International

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Background Calcineurin inhibitors (CNI) have significantly improved patient and graft survival in pediatric liver transplantation (pLT). However, CNI toxicity leads to significant morbidity. Moreover, CNIs cannot prevent long-term allograft injury. Mesenchymal stem (stromal) cells (MSC) have potent immunomodulatory properties, which may promote allograft tolerance and ameliorate toxicity of high-dose CNI. The MYSTEP1 trial aims to investigate safety and feasibility of donor-derived MSCs in pLT. Methods/Design 7 to 10 children undergoing living-donor pLT will be included in this open-label, prospective pilot trial. A dose of 1 × 106 MSCs/kg body weight will be given at two time points: first by intraportal infusion intraoperatively and second by intravenous infusion on postoperative day 2. In addition, participants will receive standard immunosuppressive treatment. Our primary objective is to assess the safety of intraportal and intravenous MSC infusion in pLT recipients. Our secondary objective is to evaluate efficacy of MSC treatment as measured by the individual need for immunosuppression and the incidence of biopsy-proven acute rejection. We will perform detailed immune monitoring to investigate immunomodulatory effects. Discussion Our study will provide information on the safety of donor-derived MSCs in pediatric living-donor liver transplantation and their effect on immunomodulation and graft survival.

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Safety and biodistribution study of bone marrow–derived mesenchymal stromal cells and mononuclear cells and the impact of the administration route in an intact porcine model

Cited by 77 publications

References 45 publications

The effect of adipose tissue-derived stem cells in a middle cerebral artery occlusion stroke model depends on their engraftment rate

The effect of adipose tissue-derived stem cells in a middle cerebral artery occlusion stroke model depends on their engraftment rate

Preclinical safety & toxicity evaluation of pooled, allogeneic human bone marrow-derived mesenchymal stromal cells

Safety and Tolerance of Donor-Derived Mesenchymal Stem Cells in Pediatric Living-Donor Liver Transplantation: The MYSTEP1 Study

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