Fate of Bone Marrow-Derived Stromal Cells after Intraperitoneal Infusion or Implantation into Femoral Bone Defects in the Host Animal

Wilson, Timothy M.; Stark, Christoffer; Holmbom, Johanna; Rosling, Ari; Kuusilehto, Asko; Tirri, Teemu; Penttinen, Risto; Ekholm, Erika

doi:10.4061/2010/345806

Cited by 29 publications

(28 citation statements)

References 36 publications

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“…This suggests that when MSC are administered via intraperitoneal injection they either die, or are dispersed widely throughout the body, the latter hypothesis being supported by other studies. [19][20][21] Other data from our laboratory have shown that intravenous infusion of MSC does not increase MSC detection (except in the lungs) (Kollar et al 2010, unpublished data), suggesting that our inability to detect MSC following intraperitoneal injection was not specifically due to the route of MSC injection. Our results demonstrate that death from GVHD can be delayed if MSC are infused post-transplant, yet MSC were not readily detected in quantities that would suggest a direct effect of MSC on wound healing, or T-cell suppression.…”

Section: Mesenchymal Stromal Cells Do Not Contribute To Healing Of Grmentioning

confidence: 66%

Mesenchymal stromal cells transiently alter the inflammatory milieu post-transplant to delay graft-versus-host disease

Christensen¹,

Turner²,

Sinfield³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundMultipotent mesenchymal stromal cells suppress T-cell function in vitro, a property that has underpinned their use in treating clinical steroid-refractory graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. However the potential of mesenchymal stromal cells to resolve graft-versus-host disease is confounded by a paucity of pre-clinical data delineating their immunomodulatory effects in vivo. Design and MethodsWe examined the influence of timing and dose of donor-derived mesenchymal stromal cells on the kinetics of graft-versus-host disease in two murine models of graft-versus-host disease (major ]) using clinically relevant conditioning regimens. We also examined the effect of mesenchymal stromal cell infusion on bone marrow and spleen cellular composition and cytokine secretion in transplant recipients. ResultsDespite T-cell suppression in vitro, mesenchymal stromal cells delayed but did not prevent graftversus-host disease in the major histocompatibility complex-mismatched model. In the sibling transplant model, however, 30% of mesenchymal stromal cell-treated mice did not develop graft-versus-host disease. The timing of administration and dose of the mesenchymal stromal cells influenced their effectiveness in attenuating graft-versus-host disease, such that a low dose of mesenchymal stromal cells administered early was more effective than a high dose of mesenchymal stromal cells given late. Compared to control-treated mice, mesenchymal stromal cell-treated mice had significant reductions in serum and splenic interferon-g, an important mediator of graft-versus-host disease. ConclusionsMesenchymal stromal cells appear to delay death from graft-versus-host disease by transiently altering the inflammatory milieu and reducing levels of interferon-g. Our data suggest that both the timing of infusion and the dose of mesenchymal stromal cells likely influence these cells' effectiveness in attenuating graft-versus-host disease.Key words: stem cell transplantation, graft-versus-host disease, mesenchymal stromal cells, IFNg.Citation: Christensen ME, Turner BE, Sinfield LL, Kollar K, Cullup H, Waterhouse NJ, Hart DNJ, Atkinson K, and Rice AM. Mesenchymal stromal cells transiently alter the inflammatory milieu posttransplant to delay graft-versus-host disease. Haematologica 2010;95(12):2102-2110. doi:10.3324/haematol.2010 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n Mesenchymal stromal cells transiently alter the inflammatory milieu post-transplant to delay graft-versus-host disease

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Section: Mesenchymal Stromal Cells Do Not Contribute To Healing Of Grmentioning

confidence: 66%

Mesenchymal stromal cells transiently alter the inflammatory milieu post-transplant to delay graft-versus-host disease

Christensen¹,

Turner²,

Sinfield³

et al. 2010

Haematologica

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“…While IP injection is a common systemic delivery route for small molecules, IP injected MSCs [76] and neuroprogenitor cells [77] were not found to migrate to other tissues. However, it is possible that lymphoid access could be achieved through this route, leading to widespread distribution of a subset of the injected cells detected by endpoint PCR [78]. In another example, MSCs were found to migrate toward an ischemic lesion of the brain when injected near the location of the ischemia and appeared, morphologically, to differentiate into microglia [79].…”

Section: Msc Delivery and Biodistributionmentioning

confidence: 99%

MSCs: Delivery Routes and Engraftment, Cell-Targeting Strategies, and Immune Modulation

Kean¹,

Lin

Caplan

et al. 2013

Stem Cells International

395

332

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Mesenchymal stem cells (MSCs) are currently being widely investigated both in the lab and in clinical trials for multiple disease states. The differentiation, trophic, and immunomodulatory characteristics of MSCs contribute to their therapeutic effects. Another often overlooked factor related to efficacy is the degree of engraftment. When reported, engraftment is generally low and transient in nature. MSC delivery methods should be tailored to the lesion being treated, which may be local or systemic, and customized to the mechanism of action of the MSCs, which can also be local or systemic. Engraftment efficiency is enhanced by using intra-arterial delivery instead of intravenous delivery, thus avoiding the “first-pass” accumulation of MSCs in the lung. Several methodologies to target MSCs to specific organs are being developed. These cell targeting methodologies focus on the modification of cell surface molecules through chemical, genetic, and coating techniques to promote selective adherence to particular organs or tissues. Future improvements in targeting and delivery methodologies to improve engraftment are expected to improve therapeutic results, extend the duration of efficacy, and reduce the effective (MSC) therapeutic dose.

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“…EPCs showed higher labeling efficiency than that of CTLs. It was not unexpected that In-111-oxine cell labeling efficiency varies with cell type [23]. Several studies showed that In111-oxine labeling of human stem cells did not affect the cell viability and stem cell characteristics [24,25].…”

Section: Discussionmentioning

confidence: 99%

“…We observed that cell associated signal from lung was higher at early time points upon systemic injection of CTLs and EPCs. Compared to other organs, lung have microvasculature, which has potential to trap injected cells based on their morphology and adhesion properties [23]. Cells like EPCs can be cleared from lung quickly compared to other cell types such as mesenchymal stem cells (MSCs), which showed higher accumulation and longer retention before redistribution into inflammation sites [23].…”

Section: Discussionmentioning

confidence: 99%

Differential biodistribution of intravenously administered endothelial progenitor and cytotoxic T-cells in rat bearing orthotopic human glioma

et al. 2013

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BackgroundA major challenge in the development of cell based therapies for glioma is to deliver optimal number of cells (therapeutic dose) to the tumor. Imaging tools such as magnetic resonance imaging (MRI), optical imaging, positron emission tomography (PET) and single-photon emission computed tomography (SPECT) has been used in cell tracking and/or biodistribution studies. In this study, we evaluate the dynamic biodistribution of systemic injected labeled cells [human cord blood derived endothelial progenitor cells (EPCs) and cytotoxic T-cells (CTLs)] in rat glioma model with in vivo SPECT imaging.MethodsHuman cord blood EPCs, T-cells and CD14+ cells (monocytes/dendritic cells) were isolated using the MidiMACS system. CD14+ cells were converted to dendritic cells (DC) and also primed with U251 tumor cell line lysate. T-cells were co-cultured with irradiated primed DCs at 10:1 ratio to make CTLs. Both EPCs and CTLs were labeled with In-111-oxine at 37°C in serum free DMEM media. Glioma bearing animals were randomly assigned into three groups. In-111 labeled cells or In-111 oxine alone were injected through tail vein and SPECT imaging was performed on day 0, 1, and 3. In-111 oxine activity in various organs and tumor area was determined. Histochemical analysis was performed to further confirm the migration and homing of injected cells at the tumor site.ResultsEPCs and CTLs showed an In-111 labeling efficiency of 87.06 ± 7.75% and 70.8 ± 12.9% respectively. Initially cell migration was observed in lung following inravenous administration of In-111 labeled cells and decreased on day 1 and 3, which indicate re-distribution of labeled cells from lung to other organs. Relatively higher In-111 oxine activity was observed in tumor areas at 24 hours in animals received In-111 labeled cells (EPCs or CTLs). Histiological analysis revealed iron positive cells in and around the tumor area in animals that received labeled cells (CTLs and EPCs).ConclusionWe observed differential biodistribution of In-111-oxine labeled EPCs and CTLs in different organs and intracranial glioma. This study indicates In-111 oxine based SPECT imaging is an effective tool to study the biodistribution of therapeutically important cells.

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Fate of Bone Marrow-Derived Stromal Cells after Intraperitoneal Infusion or Implantation into Femoral Bone Defects in the Host Animal

Cited by 29 publications

References 36 publications

Mesenchymal stromal cells transiently alter the inflammatory milieu post-transplant to delay graft-versus-host disease

Mesenchymal stromal cells transiently alter the inflammatory milieu post-transplant to delay graft-versus-host disease

MSCs: Delivery Routes and Engraftment, Cell-Targeting Strategies, and Immune Modulation

Differential biodistribution of intravenously administered endothelial progenitor and cytotoxic T-cells in rat bearing orthotopic human glioma

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