Dataset Information

Magnetically Responsive Bone Marrow Mesenchymal Stem Cell-Derived Smooth Muscle Cells Maintain Their Benefits to Augmenting Elastic Matrix Neoassembly.

ABSTRACT: Abdominal aortic aneurysms (AAA) represent abnormal aortal expansions that result from chronic proteolytic breakdown of elastin and collagen fibers by matrix metalloproteases. Poor elastogenesis by adult vascular smooth muscle cells (SMCs) limits regenerative repair of elastic fibers, critical for AAA growth arrest. Toward overcoming these limitations, we recently demonstrated significant elastogenesis by bone marrow mesenchymal stem cell-derived SMCs (BM-SMCs) and their proelastogenesis and antiproteolytic effects on rat aneurysmal SMCs (EaRASMCs). We currently investigate the effects of super paramagnetic iron oxide nanoparticle (SPION) labeling of BM-SMCs, necessary to magnetically guide them to the AAA wall, on their functional benefits. Our results indicate that SPION-labeling is noncytotoxic and does not adversely impact the phenotype and elastogenesis by BM-SMCs. In addition, SPION-BM-SMCs showed no changes in the ability of the BM-SMCs to stimulate elastin regeneration and attenuate proteolytic activity by EaRASMCs. Together, our results are promising toward the utility of SPIONs for magnetic targeting of BM-SMCs for in situ AAA regenerative repair.

SUBMITTER: Swaminathan G

PROVIDER: S-EPMC4827279 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Magnetically Responsive Bone Marrow Mesenchymal Stem Cell-Derived Smooth Muscle Cells Maintain Their Benefits to Augmenting Elastic Matrix Neoassembly.

Swaminathan Ganesh G Sivaraman Balakrishnan B Moore Lee L Zborowski Maciej M Ramamurthi Anand A

Tissue engineering. Part C, Methods 20160318 4

Abdominal aortic aneurysms (AAA) represent abnormal aortal expansions that result from chronic proteolytic breakdown of elastin and collagen fibers by matrix metalloproteases. Poor elastogenesis by adult vascular smooth muscle cells (SMCs) limits regenerative repair of elastic fibers, critical for AAA growth arrest. Toward overcoming these limitations, we recently demonstrated significant elastogenesis by bone marrow mesenchymal stem cell-derived SMCs (BM-SMCs) and their proelastogenesis and ant ...[more]

PMID: 26830683

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Project description:The chronic overexpression of matrix metalloproteases leading to consequent degradation and loss of the elastic matrix with the reduction in tissue elasticity is central to the pathophysiology of proteolytic disorders, such as abdominal aortic aneurysms (AAAs), which are localized rupture-prone aortic expansions. Effecting tissue repair to alleviate this condition is contingent on restoring elastic matrix homeostasis in the aortic wall. This is naturally irreversible due to the poor elastogenicity of adult and diseased vascular cells, and the impaired ability to assemble mature elastic fibers, more so in the context of phenotypic changes to medial smooth muscle cells (SMCs) owing to the loss of nitric oxide (NO) signaling in the AAA wall tissue. In this study, we report the benefits of the exposure of primary human aneurysmal SMCs (aHASMCs) to NO donor drug, sodium nitroprusside (SNP), in improving extracellular matrix homeostasis, particularly aspects of elastic fiber assembly, and inhibition of proteolytic degradation. SNP treatment (100 nM) upregulated elastic matrix regeneration at both gene (p < 0.05) and protein levels (p < 0.01) without affecting cell proliferation, improved gene, and protein expression of crosslinking enzyme, lysyl oxidase (p < 0.05), inhibited the expression of MMP2 (matrix metalloprotease 2) significantly (p < 0.05) and promoted contractile SMC phenotypes in aHASMC culture. In addition, SNP also attenuated the expression of mitogen-activated protein kinases, a significant player in AAA formation and progression. Our results indicate the promise of SNP for therapeutic augmentation of elastic matrix regeneration, with prospects for wall repair in AAAs. Impact Statement Chronic and naturally irreversible enzymatic degradation and loss of elastic fibers are centric to proteolytic disorders such as abdominal aortic aneurysms (AAAs). This is linked to poor elastogenicity of adult and diseased vascular cells, compromising their ability to assemble mature elastic fibers. Toward addressing this, we demonstrate the phenotype-modulatory properties of a nitric oxide donor drug, sodium nitroprusside on aneurysmal smooth muscle cells, and its dose-specific proelastogenic and antiproteolytic properties for restoring elastic matrix homeostasis. Combined with the development of vehicles for site-localized, controlled drug delivery, this can potentially lead to a new nonsurgical approach for AAA wall repair in the future.

Project description:Pulsatile chemotherapeutic delivery profiles may provide a number advantages by maximizing the anticancer toxicity of chemotherapeutics, reducing off-target side effects, and combating adaptive resistance. While these temporally dynamic deliveries have shown some promise, they have yet to be clinically deployed from implantable hydrogels, whose localized deliveries could further enhance therapeutic outcomes. Here, several pulsatile chemotherapeutic delivery profiles were tested on melanoma cell survival in vitro and compared to constant (flatline) delivery profiles of the same integrated dose. Results indicated that pulsatile delivery profiles were more efficient at killing melanoma cells than flatline deliveries. Furthermore, results suggested that parameters like the duration of drug "on" periods (pulse width), delivery rates during those periods (pulse heights), and the number/frequency of pulses could be used to optimize delivery profiles. Optimization of pulsatile profiles at tumor sites in vivo would require hydrogel materials capable of producing a wide variety of pulsatile profiles (e.g., of different pulse heights, pulse widths, and pulse numbers). This work goes on to demonstrate that magnetically responsive, biphasic ferrogels are capable of producing pulsatile mitoxantrone delivery profiles similar to those tested in vitro. Pulse parameters such as the timing and rate of delivery during "on" periods could be remotely regulated through the use of simple, hand-held magnets. The timing of pulses was controlled simply by deciding when and for how long to magnetically stimulate. The rate of release during pulse "on" periods was a function of the magnetic stimulation frequency. These findings add to the growing evidence that pulsatile chemotherapeutic delivery profiles may be therapeutically beneficial and suggest that magnetically responsive hydrogels could provide useful tools for optimizing and clinically deploying pulsatile chemotherapeutic delivery profiles.

Project description:BackgroundWithin the bone marrow (BM), mature T cells are maintained under homeostatic conditions to facilitate proper hematopoietic development. This homeostasis depends upon a peculiar elevated frequency of regulatory T cells (Tregs) and immune regulatory activities from BM-mesenchymal stem cells (BM-MSCs). In response to BM transplantation (BMT), the conditioning regimen exposes the BM to a dramatic induction of inflammatory cytokines and causes an unbalanced T-effector (Teff) and Treg ratio. This imbalance negatively impacts hematopoiesis, particularly in regard to B-cell lymphopoiesis that requires an intact cross-talk between BM-MSCs and Tregs. The mechanisms underlying the ability of BM-MSCs to restore Treg homeostasis and proper B-cell development are currently unknown.MethodsWe studied the role of host radio-resistant cell-derived CD40 in restoring Teff/Treg homeostasis and proper B-cell development in a murine model of BMT. We characterized the host cellular source of CD40 and performed radiation chimera analyses by transplanting WT or Cd40-KO with WT BM in the presence of T-reg and co-infusing WT or - Cd40-KO BM-MSCs. Residual host and donor T cell expansion and activation (cytokine production) and also the expression of Treg fitness markers and conversion to Th17 were analyzed. The presence of Cd40+ BM-MSCs was analyzed in a human setting in correlation with the frequency of B-cell precursors in patients who underwent HSCT and variably developed acute graft-versus-host (aGVDH) disease.ResultsCD40 expression is nearly undetectable in the BM, yet a Cd40-KO recipient of WT donor chimera exhibited impaired B-cell lymphopoiesis and Treg development. Lethal irradiation promotes CD40 and OX40L expression in radio-resistant BM-MSCs through the induction of pro-inflammatory cytokines. OX40L favors Teff expansion and activation at the expense of Tregs; however, the expression of CD40 dampens OX40L expression and restores Treg homeostasis, thus facilitating proper B-cell development. Indeed, in contrast to dendritic cells in secondary lymphoid organs that require CD40 triggers to express OX40L, BM-MSCs require CD40 to inhibit OX40L expression.ConclusionsCD40+ BM-MSCs are immune regulatory elements within BM. Loss of CD40 results in uncontrolled T cell activation due to a reduced number of Tregs, and B-cell development is consequently impaired. GVHD provides an example of how a loss of CD40+ BM-MSCs and a reduction in B-cell precursors may occur in a human setting.

Dataset Information

Magnetically Responsive Bone Marrow Mesenchymal Stem Cell-Derived Smooth Muscle Cells Maintain Their Benefits to Augmenting Elastic Matrix Neoassembly.

Publications

Magnetically Responsive Bone Marrow Mesenchymal Stem Cell-Derived Smooth Muscle Cells Maintain Their Benefits to Augmenting Elastic Matrix Neoassembly.

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