Fate of Intravenously Injected Mesenchymal Stem Cells and Significance for Clinical Application

Wagner, Beate; Henschler, Reinhard

doi:10.1007/10_2012_155

Cited by 30 publications

(34 citation statements)

References 81 publications

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“…Although not yet a fully validated therapy for SCI, the safety of this approach has already been established through preclinical SCI studies , its clinical application to other conditions affecting the CNS, including multiple sclerosis and bone marrow transplantations. Nevertheless, this approach is not without its limitations, osteoblastic differentiation of infused MSCs has been reported within lung tumors and although this has not been observed in injury and degeneration models, this possibility should not be dismissed. Furthermore investigation is necessary prior to clinical translation.…”

Section: Discussionmentioning

confidence: 99%

Early Intravenous Infusion of Mesenchymal Stromal Cells Exerts a Tissue Source Age-Dependent Beneficial Effect on Neurovascular Integrity and Neurobehavioral Recovery After Traumatic Cervical Spinal Cord Injury

Vawda

Badner

Hong

et al. 2019

Stem Cells Translational Medicine

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Localized vascular disruption after traumatic spinal cord injury (SCI) triggers a cascade of secondary events, including inflammation, gliosis, and scarring, that can further impact recovery. In addition to immunomodulatory and neurotrophic properties, mesenchymal stromal cells (MSCs) possess pericytic characteristics. These features make MSCs an ideal candidate for acute cell therapy targeting vascular disruption, which could reduce the severity of secondary injury, enhance tissue preservation and repair, and ultimately promote functional recovery. A moderately severe cervical clip compression/contusion injury was induced at C7‐T1 in adult female rats, followed by an intravenous tail vein infusion 1 hour post‐SCI of (a) term‐birth human umbilical cord perivascular cells (HUCPVCs); (b) first‐trimester human umbilical cord perivascular cells (FTM HUCPVCs); (c) adult bone marrow mesenchymal stem cells; or (d) vehicle control. Weekly behavioral testing was performed. Rats were sacrificed at 24 hours or 10 weeks post‐SCI and immunohistochemistry and ultrasound imaging were performed. Both term and FTM HUCPVC‐infused rats displayed improved ( p < .05) grip strength compared with vehicle controls. However, only FTM HUCPVC‐infusion led to significant weight gain. All cell infusion treatments resulted in reduced glial scarring ( p < .05). Cell infusion also led to increased axonal, myelin, and vascular densities ( p < .05). Although post‐traumatic cavity volume was reduced with cell infusion, this did not reach significance. Taken together, we demonstrate selective long‐term functional recovery alongside histological improvements with HUCPVC infusion in a clinically relevant model of cervical SCI. Our findings highlight the potential of these cells for acute therapeutic intervention after SCI.

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Section: Discussionmentioning

confidence: 99%

Early Intravenous Infusion of Mesenchymal Stromal Cells Exerts a Tissue Source Age-Dependent Beneficial Effect on Neurovascular Integrity and Neurobehavioral Recovery After Traumatic Cervical Spinal Cord Injury

Vawda

Badner

Hong

et al. 2019

Stem Cells Translational Medicine

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“…Multipotent mesenchymal stromal cells (MSCs) harbor great potential for regenerative and immunomodulatory therapies and are currently under investigation in numerous clinical trials, the majority thereof relying on systemic infusion. A major drawback in MSC therapy appears to be the incomplete understanding of fate and function of MSCs following systemic administration . Recent attention has been attributed to the fact that many MSC therapeutics are cryobanked for immediate “off‐the‐shelf” availability in the clinic .…”

Section: Introductionmentioning

confidence: 99%

Do Cryopreserved Mesenchymal Stromal Cells Display Impaired Immunomodulatory and Therapeutic Properties?

et al. 2014

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We have recently reported that therapeutic mesenchymal stromal cells (MSCs) have low engraftment and trigger the instant blood mediated inflammatory reaction (IBMIR) after systemic delivery to patients, resulting in compromised cell function. In order to optimize the product, we compared the immunomodulatory, blood regulatory, and therapeutic properties of freeze-thawed and freshly harvested cells. We found that freeze-thawed MSCs, as opposed to cells harvested from continuous cultures, have impaired immunomodulatory and blood regulatory properties. Freeze-thawed MSCs demonstrated reduced responsiveness to proinflammatory stimuli, an impaired production of anti-inflammatory mediators, increased triggering of the IBMIR, and a strong activation of the complement cascade compared to fresh cells. This resulted in twice the efficiency in lysis of thawed MSCs after 1 hour of serum exposure. We found a 50% and 80% reduction in viable cells with freshly detached as opposed to thawed in vitro cells, indicating a small benefit for fresh cells. In evaluation of clinical response, we report a trend that fresh cells, and cells of low passage, demonstrate improved clinical outcome. Patients treated with freshly harvested cells in low passage had a 100% response rate, twice the response rate of 50% observed in a comparable group of patients treated with freeze-thawed cells at higher passage. We conclude that cryobanked MSCs have reduced immunomodulatory and blood regulatory properties directly after thawing, resulting in faster complement-mediated elimination after blood exposure. These changes seem to be paired by differences in therapeutic efficacy in treatment of immune ailments after hematopoietic stem cell transplantation.

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“…Therefore, it is of high importance to elucidate how MAPC modulate the features of myeloid cell types since intravenously transplanted cells are likely to be localized in close proximity with myeloid cells in the CNS and periphery [37, 61, 69]. Overall, we showed that inflammatory macrophages are able to regulate the immunomodulatory properties of rMAPC in vitro, thereby warranting confirmatory in vivo studies.…”

Section: Discussionmentioning

confidence: 66%

Crosstalk with Inflammatory Macrophages Shapes the Regulatory Properties of Multipotent Adult Progenitor Cells

Ravanidis

Bogie

Donders

et al. 2017

Stem Cells International

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Macrophages and microglia are key effector cells in immune-mediated neuroinflammatory disorders. Driving myeloid cells towards an anti-inflammatory, tissue repair-promoting phenotype is considered a promising strategy to halt neuroinflammation and promote central nervous system (CNS) repair. In this study, we defined the impact of multipotent adult progenitor cells (MAPC), a stem cell population sharing common mesodermal origin with mesenchymal stem cells (MSCs), on the phenotype of macrophages and the reciprocal interactions between these two cell types. We show that MAPC suppress the secretion of tumor necrosis factor alpha (TNF-α) by inflammatory macrophages partially through a cyclooxygenase 2- (COX-2-) dependent mechanism. In turn, we demonstrate that inflammatory macrophages trigger the immunomodulatory properties of MAPC, including an increased expression of immunomodulatory mediators (e.g., inducible nitric oxide synthase (iNOS) and COX-2), chemokines, and chemokine receptors. Macrophage-primed MAPC secrete soluble factors that suppress TNF-α release by macrophages. Moreover, the MAPC secretome suppresses the antigen-specific proliferation of autoreactive T cells and the T cell stimulatory capacity of macrophages. Finally, MAPC increase their motility towards secreted factors of activated macrophages. Collectively, these in vitro findings reveal intimate reciprocal interactions between MAPC and inflammatory macrophages, which are of importance in the design of MAPC-based therapeutic strategies for neuroinflammatory disorders in which myeloid cells play a crucial role.

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Fate of Intravenously Injected Mesenchymal Stem Cells and Significance for Clinical Application

Cited by 30 publications

References 81 publications

Early Intravenous Infusion of Mesenchymal Stromal Cells Exerts a Tissue Source Age-Dependent Beneficial Effect on Neurovascular Integrity and Neurobehavioral Recovery After Traumatic Cervical Spinal Cord Injury

Early Intravenous Infusion of Mesenchymal Stromal Cells Exerts a Tissue Source Age-Dependent Beneficial Effect on Neurovascular Integrity and Neurobehavioral Recovery After Traumatic Cervical Spinal Cord Injury

Do Cryopreserved Mesenchymal Stromal Cells Display Impaired Immunomodulatory and Therapeutic Properties?

Crosstalk with Inflammatory Macrophages Shapes the Regulatory Properties of Multipotent Adult Progenitor Cells

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