Comparison of Transplantation of Adipose Tissue- and Bone Marrow-Derived Mesenchymal Stem Cells in the Infarcted Heart

Bogt, Koen E.A. van der; Schrepfer, Sonja; Yu, Jinhua; Sheikh, Ahmad Y.; Hoyt, Grant; Govaert, Johannes A.; Velotta, Jeffrey B.; Contag, Christopher H.; Robbins, Robert C.; Wu, Joseph C.

doi:10.1097/tp.0b013e31819609d9

Cited by 116 publications

(87 citation statements)

References 43 publications

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“…cFB injection blocked electrical impulse propagation whereas nCMs improved or maintained the electrical function of the EHT. In vivo studies have similarly reported that while fetal CMs improved cardiac function (17), noncontractile cells such as fibroblasts, or mesenchymal stem cells did not (18). As a next step, we asked whether ESC-CMs, which have been shown to exhibit some but not all of the properties of nCMs (19), would appropriately integrate into the EHT.…”

Section: Resultsmentioning

confidence: 99%

Interrogating functional integration between injected pluripotent stem cell-derived cells and surrogate cardiac tissue

Song¹,

Yoon²,

Kattman

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Myocardial infarction resulting in irreversible loss of cardiomyocytes (CMs) remains a leading cause of heart failure. Although cell transplantation has modestly improved cardiac function, major challenges including increasing cell survival, engraftment, and functional integration with host tissue, remain. Embryonic stem cells (ESCs), which can be differentiated into cardiac progenitors (CPs) and CMs, represent a candidate cell source for cardiac cell therapy. However, it is not known what specific cell type or condition is the most appropriate for transplantation. This problem is exasperated by the lack of efficient and predictive strategies to screen the large numbers of parameters that may impact cell transplantation. We used a cardiac tissue model, engineered heart tissue (EHT), and quantitative molecular and electrophysiological analyses, to test transplantation conditions and specific cell populations for their potential to functionally integrate with the host tissue. In this study, we validated our analytical platform using contractile mouse neonatal CMs (nCMs) and noncontractile cardiac fibroblasts (cFBs), and screened for the integration potential of ESC-derived CMs and CPs (ESC-CMs and -CPs). Consistent with previous in vivo studies, cFB injection interfered with electrical signal propagation, whereas injected nCMs improved tissue function. Purified bioreactor-generated ESC-CMs exhibited a diminished capacity for electrophysiological integration; a result correlated with lower (compared with nCMs) connexin 43 expression. ESC-CPs, however, appeared able to appropriately mature and integrate into EHT, enhancing the amplitude of tissue contraction. Our results support the use of EHT as a model system to accelerate development of cardiac cell therapy strategies.

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Section: Resultsmentioning

confidence: 99%

Interrogating functional integration between injected pluripotent stem cell-derived cells and surrogate cardiac tissue

Song¹,

Yoon²,

Kattman

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Matrix-associated stem cell implants (MASIs) have a high potential for bone and cartilage regeneration (3,4). However, a major challenge of current approaches is death of the transplanted cells because of failed engraftment and/ or immune rejection (5,6). In case of graft failure, the transplanted cells die first (eg, because of hypoxia or mechanical factors), which leads to secondary macrophage influx and clearance of dead cells (7).…”

Section: Contrast Agentmentioning

confidence: 99%

Intravenous Ferumoxytol Allows Noninvasive MR Imaging Monitoring of Macrophage Migration into Stem Cell Transplants

Khurana¹,

Nejadnik²,

Gawande³

et al. 2012

Radiology

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Purpose:To develop a clinically applicable imaging technique for monitoring differential migration of macrophages into viable and apoptotic matrix-associated stem cell implants (MASIs) in arthritic knee joints. Materials andMethods:With institutional animal care and use committee approval, six athymic rats were injected with intravenous ferumoxytol (0.5 mmol iron per kilogram of body weight) to preload macrophages of the reticuloendothelial system with iron oxide nanoparticles. Forty-eight hours later, all animals received MASIs of viable adipose-derived stem cells (ADSCs) in an osteochondral defect of the right femur and mitomycin-pretreated apoptotic ADSCs in an osteochondral defect of the left femur. One additional control animal each received intravenous ferumoxytol and bilateral scaffold-only implants (without cells) or bilateral MASIs without prior ferumoxytol injection. All knees were imaged with a 7.0-T magnetic resonance (MR) imaging unit with T2-weighted fast spin-echo sequences immediately after, as well as 2 and 4 weeks after, matrix-associated stem cell implantation. Signal-to-noise ratios (SNRs) of viable and apoptotic MASIs were compared by using a linear mixedeffects model. MR imaging data were correlated with histopathologic findings. Results:All ADSC implants showed a slowly decreasing T2 signal over 4 weeks after matrix-associated stem cell implantation. SNRs decreased significantly over time for the apoptotic implants (SNRs on the day of matrix-associated stem cell implantation, 2 weeks after the procedure, and 4 weeks after the procedure were 16.9, 10.9, and 6.7, respectively; P = .0004) but not for the viable implants (SNRs on the day of matrix-associated stem cell implantation, 2 weeks after the procedure, and 4 weeks after the procedure were 17.7, 16.2, and 15.7, respectively; P = .2218). At 4 weeks after matrix-associated stem cell implantation, SNRs of apoptotic ADSCs were significantly lower than those of viable ADSCs (mean, 6.7 vs 15.7; P = .0013). This corresponded to differential migration of ironloaded macrophages into MASIs. Conclusion:Iron oxide loading of macrophages in the reticuloendothelial system by means of intravenous ferumoxytol injection can be utilized to monitor differential migration of bone marrow macrophages into viable and apoptotic MASIs in a rat model.

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“…Although MSCs have positive effects via production of growth factors favoring angiogenesis, 1 increase of antiapoptotic molecules, and suppression of inflammation, 2 these positive effects occur in the short timeframe between implantation and death of MSCs. 3 The loss in the implanted MSC numbers has been reported for implantation of several tissues using different implantation methods, including injection into the inflammatory bowel 4 and the infarcted hearts, 5,6 or implantation into the injured bone 7 and the ischemic kidney. 8 The disappearance of MSCs is closely associated with death-inducing conditions such as increased reactive oxygen species, 9 hypoxia, 10 and nutrient deprivation 11 in the wound environment along with nonspecific inflammation generated in response to implantation of any foreign material into the body.…”

Section: Introductionmentioning

confidence: 99%

The Matrikine Tenascin-C Protects Multipotential Stromal Cells/Mesenchymal Stem Cells from Death Cytokines Such as FasL

Rodrigues

Yates

Nuschke

et al. 2013

Tissue Engineering Part A

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Multipotential stromal cells/mesenchymal stem cells (MSCs) are attractive candidates for regenerative therapy due to the ability of these cells to differentiate and positively influence neighboring cells. However, on implantation for wound reconstruction, these cells are lost as they are challenged by nonspecific inflammation signals generated in the wound environment and in response to any implanted foreign body. We have previously shown that sustained and surface-restricted epidermal growth factor receptor (EGFR) signaling by a tethered form of its prototypal ligand EGF enhances survival of MSC in the presence of death cytokines such as FasL, serum deprivation, and low oxygen in vitro. This was proposed to be due to the plasma membrane restriction of EGFR signaling. Interestingly, during wound repair, an extracellular matrix (ECM) component Tenascin-C (TNC) containing EGF-like repeats (EGFL) and fibronectin-like repeats (FNL) is upregulated. A few of the 14 EGFL on each of the 6 arms, especially the 14th, bind as low-affinity/high-avidity ligands to EGFR causing sustained surface-restricted EGFR signaling. We queried whether signaling by this physiologically relevant EGFR matrikine also protects MSCs from FasLinduced death. MSCs grown on TNC and Collagen I (as TNC by itself is antiadhesive) displayed a survival advantage in the presence of FasL. TNC neither sequestered nor neutralized FasL; rather, the effects of survival were via cell signaling. This survival was dependent on TNC activating EGFR and downstream pathways of Erk and Akt through EGFL; to a much lesser extent, the FNL of TNC also contributed to survival. Taken together, these results suggest that providing MSCs with a nonimmunogenic naturally occurring ECM moiety such as TNC enhances their survival in the presence of death factors, and this advantage occurs via signaling through EGFR primarily and integrins only to a minor extent. This matrix component is proposed to supplement MSC delivery on the scaffolds to provide a survival advantage against death upon in vivo implantation.

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Comparison of Transplantation of Adipose Tissue- and Bone Marrow-Derived Mesenchymal Stem Cells in the Infarcted Heart

Cited by 116 publications

References 43 publications

Interrogating functional integration between injected pluripotent stem cell-derived cells and surrogate cardiac tissue

Interrogating functional integration between injected pluripotent stem cell-derived cells and surrogate cardiac tissue

Intravenous Ferumoxytol Allows Noninvasive MR Imaging Monitoring of Macrophage Migration into Stem Cell Transplants

The Matrikine Tenascin-C Protects Multipotential Stromal Cells/Mesenchymal Stem Cells from Death Cytokines Such as FasL

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