Biodistribution and Clearance of Human Mesenchymal Stem Cells by Quantitative Three-Dimensional Cryo-Imaging After Intravenous Infusion in a Rat Lung Injury Model

Schmuck, Eric G.; Koch, Jill M.; Centanni, John M.; Hacker, Timothy A.; Braun, Ruedi K.; Eldridge, Marlowe; Hei, Derek J.; Hematti, Peiman; Raval, Amish N.

doi:10.5966/sctm.2015-0379

Cited by 43 publications

(34 citation statements)

References 52 publications

(66 reference statements)

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“…Finally, to further confirm that these vimentin-positive cells are hUC-MSC, lung sections were immunolabeled with anti-human CD105 and anti-HLA-1 antibodies, which also showed similar positive cells ( Fig 13 ). Taken together, our results are consistent with previous reports[ 18 , 37 – 39 ] indicating homing of MSC in mouse lungs within the first 24 hours from systemic intravenous administration, followed by a fast dislodgement afterwards.…”

Section: Resultssupporting

confidence: 94%

Mesenchymal stromal cells from human umbilical cord prevent the development of lung fibrosis in immunocompetent mice

et al. 2018

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Lung fibrosis is a severe condition resulting from several interstial lung diseases (ILD) with different etiologies. Current therapy of ILD, especially those associated with connective tissue diseases, is rather limited and new anti-fibrotic strategies are needed. In this study, we investigated the anti-fibrotic activity in vivo of human mesenchymal stromal cells obtained from whole umbilical cord (hUC-MSC). Adult immunocompetent C57BL/6 mice (n. = 8 for each experimental condition) were injected intravenously with hUC-MSC (n. = 2.5 × 105) twice, 24 hours and 7 days after endotracheal injection of bleomycin. Upon sacrifice at days 8, 14, 21, collagen content, inflammatory cytokine profile, and hUC-MSC presence in explanted lung tissue were analyzed. Systemic administration of a double dose of hUC-MSC significantly reduced bleomycin-induced lung injury (inflammation and fibrosis) in mice through a selective inhibition of the IL6-IL10-TGFβ axis involving lung M2 macrophages. Only few hUC-MSC were detected from explanted lungs, suggesting a “hit and run” mechanism of action of this cellular therapy. Our data indicate that hUC-MSC possess strong in vivo anti-fibrotic activity in a mouse model resembling an immunocompetent human subject affected by inflammatory ILD, providing proof of concept for ad-hoc clinical trials.

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Section: Resultssupporting

confidence: 94%

Mesenchymal stromal cells from human umbilical cord prevent the development of lung fibrosis in immunocompetent mice

et al. 2018

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“…The IM injected cells were found to be restricted within the injection site in the highly vascular muscle. In contrast, in systemic cell intravenous delivery, the cells are immediately trapped in the lungs, as previously reported with other stromal cells …”

Section: Discussionsupporting

confidence: 63%

“…In contrast, in systemic cell intravenous delivery, the cells are immediately trapped in the lungs, as previously reported with other stromal cells. 26,36,57 The increased survival of the high dose irradiated mice treated with PLX-RAD was found to be associated with highly significant accelerated recovery of BM. This resulted in the fast increase of peripheral blood cells counts within the critical life-threatening period of radiation induced pancytopenia, relative to much lower regeneration in non-treated irradiated controls.…”

Section: Discussionmentioning

confidence: 97%

“…55,56 It was previously reported that intravenously injected cells, particularly stromal cells, such as BM-MSCs, are predominantly trapped in the lung immediately following their administration. 36,57 In contrast, intramuscular (IM) injection allows the delivery of higher numbers of cells, which remain within the area of the injection site for at least 1-3 weeks with no apparent adverse effects. 26 Therefore, the apparently complication-free IM cell delivery was adopted for the current study.…”

Section: Introductionmentioning

confidence: 99%

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Rescue from lethal acute radiation syndrome (ARS) with severe weight loss by secretome of intramuscularly injected human placental stromal cells

Pinzur

Akyuez

Levdansky

et al. 2018

J cachexia sarcopenia muscle

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BackgroundMost current cell‐based regenerative therapies are based on the indirect induction of the affected tissues repair. Xenogeneic cell‐based treatment with expanded human placenta stromal cells, predominantly from fetal origin (PLX‐RAD cells), were shown to mitigate significantly acute radiation syndrome (ARS) following high dose irradiation in mice, with expedited regain of weight loss and haematopoietic function. The current mechanistic study explores the indirect effect of the secretome of PLX‐RAD cells in the rescue of the irradiated mice.MethodsThe mitigation of the ARS was investigated following two intramuscularly (IM) injected 2 × 106 PLX‐RAD cells, 1 and 5 days following 7.7 Gy irradiation. The mice survival rate and their blood or bone marrow (BM) cell counts were followed up and correlated with multiplex immunoassay of a panel of related human proteins of PLX‐RAD derived secretome, as well as endogenous secretion of related mouse proteins. PLX‐RAD secretome was also tested in vitro for its effect on the induction of the migration of BM progenitors.ResultsA 7.7 Gy whole body mice irradiation resulted in ~25% survival by 21 days. Treatment with two IM injections of 2 × 106 PLX‐RAD cells on days 1 and 5 after irradiation mitigated highly significantly the subsequent lethal ARS, with survival rate increase to nearly 100% and fast regain of the initial weight loss (P < 0,0001). This was associated with a significant faster haematopoiesis recovery from day 9 onwards (P < 0.01). Nine out of the 65 human proteins tested were highly significantly elevated in the mouse circulation, peaking on days 6–9 after irradiation, relative to negligible levels in non‐irradiated PLX‐RAD injected mice (P < 0.01). The highly elevated proteins included human G‐CSF, GRO, MCP‐1, IL‐6 and lL‐8, reaching >500 pg/mL, while MCP‐3, ENA, Eotaxin and fractalkine levels ranged between ~60–160pg/mL. The detected radiation‐induced PLX‐RAD secretome correlated well with the timing of the fast haematopoiesis regeneration. The radiation‐induced PLX‐RAD secretome seemed to reinforce the delayed high levels secretion of related mouse endogenous cytokines, including GCSF, KC, MCP‐1 and IL‐6. Additional supportive in vitro studies also confirmed the ability of cultured PLX‐RAD secretome to induce accelerated migration of BM progenitors.ConclusionsA well‐regulated and orchestrated secretion of major pro‐regenerative BM supporting secretome in high dose irradiated mice, treated with xenogeneic IM injected PLX‐RAD cells, can explain the observed mitigation of ARS. This seemed to coincide with faster haematopoiesis regeneration, regain of severe weight loss and the increased survival rate. The ARS‐related stress signals activating the IM injected PLX‐RAD cells for the remote secretion of the relevant human proteins deserve further investigation.

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“…Since MSC has the characteristics of chemotaxis to damaged tissue and organ parts, the metabolic kinetics of MSCs is different between the healthy body and the disease body. After the peripheral intravenous injection, most of the MSCs remained in the lungs and then reached the liver, kidney and spleen along with the blood flow [52,53]. In another report, the autologous bone marrow MSCs of the patients with decompensated cirrhosis were amplified in vitro, and were infused via peripheral vein, the results showed that the lung stranded MSCs gradually migrated from lung to liver and spleen with the extension of time, and there are more cells in the spleen than in the liver [54].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells modified by FGF21 and GLP1 ameliorate lipid metabolism while reducing blood glucose in type 2 diabetic mice

Xue¹,

Xiao

Yu³

et al. 2020

Preprint

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Objective: The purpose of the study was to investigate the therapeutic effects and safety of genetic modified mesenchymal stem cells (MSCs) in type 2 diabetes mellitues (T2DM).Methods: MSCs derived from adipose tissue were modified with over-expression of FGF21 and GLP1, which was achieved through lentiviral particles transduction. The cells were transplanted to the BKS.Cg-Dock7m+/+Leprdb/Nju mice (T2DM mice model). The injections of physiological saline (0.1 mL), Liraglutide (0.5mg/kg) were employed as negative and positive controls respectively. The protein analyses were performed using ELISA or western blot analysis, while quantitative real-time PCR was adopted for gene expression.Results: The genetic modification had no effects on morphology, differentiation ability, or immunophenotype of MSCs. Moreover, MSC-FGF21+GLP1 cells exhibited significantly increased expression of FGF21 and GLP1. In T2DM model mice, the transplantation of MSC-FGF21+GLP1 cells ameliorated blood glucose and weight, promoted the secretion of insulin, enhanced the recovery of liver structures, and improved lipid profiles. Moreover, FGF21 and GLP1 exhibited synergistic effects in regulation of glucolipid metabolism through controlling the expression of insulin, srebp1 and srebp2.Conclusion: The stem cell treatment based on MSCs modified by FGF21 and GLP1 genes is an effective approach for treatment of T2DM.

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Biodistribution and Clearance of Human Mesenchymal Stem Cells by Quantitative Three-Dimensional Cryo-Imaging After Intravenous Infusion in a Rat Lung Injury Model

Cited by 43 publications

References 52 publications

Mesenchymal stromal cells from human umbilical cord prevent the development of lung fibrosis in immunocompetent mice

Mesenchymal stromal cells from human umbilical cord prevent the development of lung fibrosis in immunocompetent mice

Rescue from lethal acute radiation syndrome (ARS) with severe weight loss by secretome of intramuscularly injected human placental stromal cells

Mesenchymal stem cells modified by FGF21 and GLP1 ameliorate lipid metabolism while reducing blood glucose in type 2 diabetic mice

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