Antiproliferative Effects of Local Anesthetics on Mesenchymal Stem Cells

Lucchinetti, Eliana; Awad, Ahmed; Rahman, Mamoona; Feng, Jianhua; Lou, Phing‐How; Zhang, Liyan; Ionescu, Lavinia; Lemieux, Hélène; Thébaud, Bernard; Zaugg, Michael

doi:10.1097/aln.0b013e31824babfe

Cited by 132 publications

(55 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, multiple studies have demonstrated that common amide LA, such as bupivacaine, have cytotoxic effects in potency-, concentration-, and time-dependent manners on neurons [4] and non-target cells such as chondrocytes [5, 6], fibroblasts [7], and macrophages [8]; which indicates that LA could significantly affect healing and regeneration processes. Therefore, as mesenchymal stromal cell (MSC) therapies become more popular treatment options for a wide range of diseases and traumatic injuries such as autoimmune conditions, wound healing, osteoarthritis, and neurodegenerative disorders and traumas [9], the interest in understanding the effects of co-administered LA has increased [5, 10, 11]. …”

Section: Introductionmentioning

confidence: 99%

Alginate-liposomal construct for bupivacaine delivery and MSC function regulation

Davis

Marrero-Berríos

Perez

et al. 2017

Drug Deliv. and Transl. Res.

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

Alginate-liposomal construct for bupivacaine delivery and MSC function regulation

Davis

Marrero-Berríos

Perez

et al. 2017

Drug Deliv. and Transl. Res.

View full text Add to dashboard Cite

show abstract

“…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%

“…1-6 We and others have demonstrated that MSCs respond to their microenvironment and play an important role in promoting tissue regeneration in part by attenuating pro-inflammatory macrophage secretion of tumor necrosis factor (TNF)-α via production of prostaglandin E2 (PGE2). 7 Progression of OA occurs in conjunction with an increase in pro-inflammatory (M1) macrophages which not only exacerbate articular damage, but also reduce the chondrogenic potential of implanted MSCs.…”

Section: Introductionmentioning

confidence: 99%

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

Gray

Marrero-Berríos

Weinberg

et al. 2016

International Immunopharmacology

View full text Add to dashboard Cite

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.

show abstract

“…Modern local anesthetics (lidocaine (Johns et al, 1985) and bupivacaine (Johns et al, 1986)) have a dose dependent biphasic effect: low concentrations cause vasoconstriction of arterioles, while high concentrations cause vasodilation. Local anesthetics can be detrimental to angiogenesis by an anti-proliferative effect on mesenchymal cells (Lucchinetti et al, 2012). However, local anesthetics may have an overall positive influence on the microcirculation by reducing the stress response associated with pain (Bamigboye and Hofmeyr, 2009).…”

Section: Interventions That Influence the Aging Microcirculationmentioning

confidence: 99%

The effect of aging on the cutaneous microvasculature

Bentov

Reed

2015

Microvascular Research

View full text Add to dashboard Cite

Aging is associated with a progressive loss of function in all organs. Under normal conditions the physiologic compensation for age-related deficits is sufficient, but during times of stress the limitations of this reserve become evident. Explanations for this reduction in reserve include the changes in the microcirculation that occur during the normal aging process. The microcirculation is defined as the blood flow through arterioles, capillaries and venules, which are the smallest vessels in the vasculature and are embedded within organs and tissues. Optimal strategies to maintain the microvasculature following surgery and other stressors must use multifactorial approaches. Using skin as the model organ, we will review the anatomical and functional changes in the microcirculation with aging, and some of the available clinical strategies to potentially mitigate the effect of these changes on important clinical outcomes.

show abstract

Antiproliferative Effects of Local Anesthetics on Mesenchymal Stem Cells

Cited by 132 publications

References 51 publications

Alginate-liposomal construct for bupivacaine delivery and MSC function regulation

Alginate-liposomal construct for bupivacaine delivery and MSC function regulation

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

The effect of aging on the cutaneous microvasculature

Contact Info

Product

Resources

About