Effect of Local Anesthetics on Human Mesenchymal Stromal Cell Secretion

Gray, Andrea; Marrero-Berríos, Ileana; Ghodbane, Mehdi; Maguire, Timothy J.; Weinberg, Jonathan; Manchikalapati, Devasena; SchianodiCola, Joseph; Schloss, Rene; Yarmush, Joel

doi:10.1142/s1793984415500014

Cited by 12 publications

(34 citation statements)

References 42 publications

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“…The MSC-alginate constructs so generated, expressed immunomodulatory capacity. This confirms the recent studies of Stucky and co-workers, demonstrating an inhibition of neuro-inflammation by MSCs that were encapsulated in alginate for 1 d, and Gray and coworkers, demonstrating secretion of factors in reaction to inflammatory cytokines after 2 d of encapsulation in alginate (Gray et al, 2015;Stucky et al, 2015). We demonstrate, in this study, that MSC encapsulated in alginate can inhibit T cell proliferation.…”

Section: Mjc Leijs Et Al Encapsulation Of Mscs In Alginatesupporting

confidence: 89%

Encapsulation of allogeneic mesenchymal stem cells in alginate extends local presence and therapeutic function

Leijs¹,

Villafuertes²,

Haeck³

et al. 2017

eCM

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Bone marrow derived mesenchymal stem cells (MSCs) have immunomodulatory and trophic capacities. For therapeutic application in local chronic inflammatory diseases, MSCs, preferably of allogeneic origin, have to retain immunomodulatory properties. This might be achieved by encapsulation of MSCs in a biomaterial that protects them from the host immune system. Most studies investigating the properties of MSCs for therapeutic application use short term cultures of cells in monolayer.Since the physical environment of MSCs can influence their functionality, we evaluated the feasibility of preserving the immunomodulatory properties of MSCs encapsulated in a three-dimensional alginate construct.After 5 weeks of implantation in immunocompetent rats, active allogeneic MSCs encapsulated in alginate were still detectable by Bio Luminescence Imaging and Magnetic Resonance Imaging of luciferase transduced and superparamagnetic iron oxide labelled MSCs. MSCs injected in saline were only detectable up to 1 week after injection. Moreover, the MSCs encapsulated in alginate responded to inflammatory stimuli similarly to MSCs in monolayer culture. In addition, MSC-alginate beads secreted immunomodulatory and trophic factors and inhibited T-cell proliferation after 30 d of in vitro culture. Our data indicate that allogeneic MSCs encapsulated in alginate persist locally and could act as an interactive immunomodulatory or trophic factor release system for several weeks, making this an interesting system to investigate for application in inflammatory disease conditions.

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Section: Mjc Leijs Et Al Encapsulation Of Mscs In Alginatesupporting

confidence: 89%

Encapsulation of allogeneic mesenchymal stem cells in alginate extends local presence and therapeutic function

Leijs¹,

Villafuertes²,

Haeck³

et al. 2017

eCM

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“…7 In addition, we previously observed that a high concentration (1 mM) of lidocaine or bupivacaine resulted in decreased constitutive secretion of PGE2 by monolayer MSCs. 18 Therefore, we next characterized the effect of LAs on PGE2 levels in the co-culture of macrophages and MSCs. Levels of PGE2 detected from macrophages alone with and without LAs were low relative to co-cultures of macrophages and MSCs, suggesting that the MSCs were the main source of PGE2 ( Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…For comparative purposes, LA and LPS concentrations were selected based on previous in vitro studies performed by our group and others. 6, 7, 15, 18-23 .…”

Section: Methodsmentioning

confidence: 99%

“…Viability was assessed using an alamar blue assay, as described previously. 18 Briefly, after culture in the presence of the local anesthetics, the culture supernatants were gently collected, stored at −80°C, and replaced with fresh medium containing alamar blue reagent (alamarBlue, Life Technologies, Carlsbad, CA) according to the manufacturer’s instructions. The fluorescence of the wells was read after 4 hours of incubation using a microplate reader (DTX 880 Multimode Detector, Beckman Coulter, Fullerton, CA).…”

Section: Methodsmentioning

confidence: 99%

“…18 Using a previously established macrophage/MSC co-culture assay for MSC anti-inflammatory function, 7 the current studies were designed to assess the in vitro effects of two commonly used lower or higher potency LAs, lidocaine and bupivacaine respectively, on lipopolysaccharide (LPS)-activated M1 macrophages and MSC attenuation of inflammation. Our results indicate that LA can inhibit MSC anti-inflammatory function either directly or by modulating the inflammatory microenvironment, and in concert reduce MSC efficacy even after LA withdrawal.…”

Section: Introductionmentioning

confidence: 99%

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The effect of local anesthetic on pro-inflammatory macrophage modulation by mesenchymal stromal cells

Gray

Marrero-Berríos

Weinberg

et al. 2016

International Immunopharmacology

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Administering local anesthetics (LAs) peri- and post-operatively aims to prevent or mitigate pain in surgical procedures and after tissue injury in cases of osteoarthritis (OA) and other degenerative diseases. Innovative tissue protective and reparative therapeutic interventions such as mesenchymal stromal cells (MSCs) are likely to be exposed to co-administered drugs such as LAs. Therefore, it is important to determine how this exposure affects the therapeutic functions of MSCs and other cells in their target microenvironment. In these studies, we measured the effect of LAs, lidocaine and bupivacaine, on macrophage viability and pro-inflammatory secretion. We also examined their effect on modulation of the macrophage pro-inflammatory phenotype in an in vitro co-culture system with MSCs, by quantifying macrophage tumor necrosis factor (TNF)-α secretion and MSC prostaglandin E2 (PGE2) production. Our studies indicate that both LAs directly attenuated macrophage TNF-α secretion, without significantly affecting viability, in a concentration- and potency-dependent manner. LA-mediated attenuation of macrophage TNF-α was sustained in co-culture with MSCs, but MSCs did not further enhance this anti-inflammatory effect. Concentration- and potency-dependent reductions in macrophage TNF-α were concurrent with decreased PGE2 levels in the co-cultures further indicating MSC-independent macrophage attenuation. MSC functional recovery from LA exposure was assessed by pre-treating MSCs with LAs prior to co-culture with macrophages. Both MSC attenuation of TNF-α and PGE2 secretion were impaired by pre-exposure to the more potent bupivacaine and high dose of lidocaine in a concentration-dependent manner. Therefore, LAs can affect anti-inflammatory function by both directly attenuating macrophage inflammation and MSC secretion and possibly by altering the local microenvironment which can secondarily reduce MSC function. Furthermore, the LA effect on MSC function may persist even after LA removal.

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Alginate-liposomal construct for bupivacaine delivery and MSC function regulation

Davis

Marrero-Berríos

Perez

et al. 2017

Drug Deliv. and Transl. Res.

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Mesenchymal stromal cell (MSC) therapies have become potential treatment options for multiple ailments and traumatic injuries. In the clinical setting, MSC are likely to be co-administered with local anesthetics (LA) which have been shown to have dose- and potency-dependent detrimental effects on the viability and function of cells. We previously developed and characterized a sustained-release LA delivery formulation comprised of alginate-encapsulated liposomal bupivacaine. The current studies were designed to evaluate the effect of this formulation on the secretion of three key MSC regulatory molecules, interleukin 6 (IL-6), prostaglandin E2 (PGE2), and transforming growth factor-beta 1 (TGF-β1). MSCs were treated with several bupivacaine formulations—bolus, liposome, or alginate-liposome construct (engineered construct)—in the presence or absence of inflammatory stimulus to stimulate an injured tissue environment. Our results indicated that compared to bolus or liposomal bupivacaine, the engineered construct preserved or promoted MSC anti-inflammatory PGE2 secretion; however, the engineered construct did not increase TGF-β1 secretion. Bupivacaine release profile analyses indicated that mode of drug delivery controlled the LA concentration over time and pathway analysis identified several shared and cytokine-specific molecular mediators for IL-6, PGE2, and TGF-β1 which could explain differential MSC secretion responses in the presence of bupivacaine. Collectively, these studies support the potential utility of alginate-encapsulated LA constructs for anti-inflammatory cell therapy co-administration and indicate that mode of local anesthetic delivery can significantly alter MSC secretome function.

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Effect of Local Anesthetics on Human Mesenchymal Stromal Cell Secretion

Cited by 12 publications

References 42 publications

Encapsulation of allogeneic mesenchymal stem cells in alginate extends local presence and therapeutic function

Encapsulation of allogeneic mesenchymal stem cells in alginate extends local presence and therapeutic function

The effect of local anesthetic on pro-inflammatory macrophage modulation by mesenchymal stromal cells

Alginate-liposomal construct for bupivacaine delivery and MSC function regulation

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