Serum-Free Medium Enhances the Immunosuppressive and Antifibrotic Abilities of Mesenchymal Stem Cells Utilized in Experimental Renal Fibrosis

Yoshida, Ken; Nakashima, Ayumu; Doi, Shigehiro; Ueno, Toshinori; Okubo, Tomoe; Kawano, Ki ichiro; Kanawa, Masami; Kato, Yukio; Higashi, Yukihito; Takao, Masaki

doi:10.1002/sctm.17-0284

Cited by 44 publications

(72 citation statements)

References 58 publications

(81 reference statements)

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“…PGE2 also induced the polarization of immunosuppressive M2 macrophages that produce anti-inflammatory cytokines and inhibit the persistence of inflammation [26,27]. In addition, we previously reported that MSCs promoted macrophage differentiation from an M1 pro-inflammatory phenotype to an immunosuppressive M2 phenotype, and that the administration of ex vivo-expanded MSCs suppressed the progression of fibrosis [28,29]. Taken together, this suggests that IFN-γ-preconditioned MSCs have a strong immunosuppressive effect and therefore might ameliorate renal fibrosis.…”

Section: Introductionmentioning

confidence: 78%

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IFN-γ Enhances the Therapeutic Effect of Mscs on Experimental Renal Fibrosis

Kanai

Nakashima

Doi

et al. 2020

Preprint

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Background:Mesenchymal stem cells (MSCs) administered for therapeutic purposes can be activated by interferon-γ (IFN-γ) secreted from natural killer cells in injured tissues and exert anti-inflammatory effects. These processes may require a substantial period of time, leading to a delayed onset of MSCs therapeutic effects. Here, we investigatedwhetherpretreatment with IFN-γ potentiates the anti-fibrotic and anti-inflammatory activities of MSCs in an injured kidney. Methods:MSCs with or without IFN-γ treatment were injected into rats after ischemia-reperfusion injury (IRI) or unilateral ureter obstruction (UUO) to evaluate the therapeutic effect of IFN-γ-treated MSCs. In addition, we used conditioned medium obtained from IFN-γ-treated MSCs to investigate fibrotic change in cultured cells induced by transforming growth factor-β1 and phenotypic change of macrophages using THP-1 monocytes.Results:Administration of MSCs treated with IFN-γ strongly ameliorated renal fibrosis and inflammation in rat IRI and UUO models compared with that of untreated MSCs. In vitro experiments demonstrated that IFN-γ treatment enhanced the anti-fibrotic effects of MSCs by inhibiting the transforming growth factor-β1/Smad signaling pathway. Most notably, secretion of prostaglandin E2 from MSCs was significantly increased by treatment with IFN-γ. Increased prostaglandin E2 induced polarization of immunosuppressive CD163-positive macrophages. In addition, knockdown of prostaglandin E synthase weakened the anti-fibrotic effects of MSCs treated with IFN-γ in IRI rats, suggesting the involvement of prostaglandin E2 in the beneficial effects of IFN-γ.Conclusions:Administration of MSCs treated with IFN-γ may represent a promising therapy to prevent the progression of renal fibrosis.

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Section: Introductionmentioning

confidence: 78%

“…HK-2 cells, a human proximal tubular cell line, were obtained from the American Type Culture Collection (Manassas, VA). These cells were cultured as described previously [28].…”

Section: Cell Culturementioning

confidence: 99%

IFN-γ Enhances the Therapeutic Effect of Mscs on Experimental Renal Fibrosis

Kanai

Nakashima

Doi

et al. 2020

Preprint

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“…The cell-free CM derived from MSCs is enriched in various soluble factors, including growth factors, immunomodulatory molecules, cytokines, and chemokines [40,48,49]. MSC-derived CM has shown to have beneficial effects both in vivo and in vitro [50][51][52][53]. In addition, preconditioning strategies such as the environmental variations and stimulatory conditions of MSCs can change the composition of CM active factors and influence the CM's therapeutic effect.…”

Section: Msc-derived CMmentioning

confidence: 99%

Mesenchymal stem cell-derived secretomes for therapeutic potential of premature infant diseases

et al. 2020

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Preterm birth is a complex syndrome and remains a substantial public health problem globally. Its common complications include periventricular leukomalacia (PVL), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC) and retinopathy of prematurity (ROP). Despite great advances in the comprehension of the pathogenesis and improvements in neonatal intensive care and associated medicine, preterm birth-related diseases remain essentially without adequate treatment and can lead to high morbidity and mortality. The therapeutic potential of mesenchymal stem/stromal cells (MSCs) appears promising as evidenced by their efficacy in preclinical models of pathologies relevant to premature infant complications. MSC-based therapeutic efficacy is closely associated with MSC secretomes and a subsequent paracrine action response to tissue injuries, which are complex and abundant in response to the local microenvironment. In the current review, we summarize the paracrine mechanisms of MSC secretomes underlying diverse preterm birth-related diseases, including PVL, BPD, NEC and ROP, are summarized, and focus is placed on MSC-conditioned media (CM) and MSC-derived extracellular vesicles (EVs) as key mediators of modulatory action, thereby providing new insights for future therapies in newborn medicine.lung function and help to remove the ventilator as soon as possible [12]. However, many studies have reported that glucocorticoid can increase the risk of adverse reactions, such as those by the nervous system, in the early or late stages, and its dose and course of treatment are not certain [13,14]. In terms of surgical treatment, preterm infants with surgical NEC are at risk of significant growth reduction and neurodevelopmental impairment (NDI), including cerebral palsy, deafness and blindness [15,16]. These sequelae and complications of prematurity-related diseases affect not only the neonatal period, but also infancy and childhood, and even adolescence and adulthood [17][18][19]. Currently, although various treatment methods have been found to achieve certain curative effects, there still exist several side effects and disputes above. Thus, it is necessary to explore and develop new therapies for the treatment and prevention of premature infant diseases.Accumulating studies have established the importance and feasibility of stem cell-based therapies to ameliorate many degenerative and inflammatory diseases. Among these stem/progenitor cell types, mesenchymal stem/stromal cells (MSCs) have received more extensive attention because they are easily extracted, exert anti-inflammatory effects, have low immunogenicity and can renew themselves. The therapeutic potential of MSCs has been demonstrated in many diseases such as cancer [20,21] and cardiovascular [22,23] and lung [24][25][26] diseases. MSCs also represent a promising and growing approach to the targeting of various pathological processes and cellular impairments underlying the major abnormalities in premature infant and preterm-associated neonatal diseases [27][28]...

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“…However, most ex vivo expanded MSC have been grown in animal‐derived serum, which presents potential dangers for their use in human applications, and using autologous human serum is impractical and often impossible. A new report in Stem Cells Translational Medicine compares the effects of MSC grown in serum‐free (SF‐MSC) or 10% fetal bovine serum (FBS; 10% MSC) on inflammation and fibrosis in a renal fibrosis model . Yoshida et al used UUO rats treated with SF‐MSC, which showed decreases in profibrotic markers in immunostained kidney sections compared with the 10%‐MSC‐treated groups.…”

Section: Related Publicationsmentioning

confidence: 99%

“…This article highlights the promising approach of re‐activating an inherent quality of innate cells to enable tissue regeneration. In a related article, Yoshida et al compared the impact of serum‐free and standard serum‐containing MSC growth conditions in a rat model of tubulointerstitial fibrosis and found that serum‐free ex vivo expansion may further enhance immunosuppressive properties of MSC . Amplifying the regenerative properties of MSC is another potential approach used to strengthen the fundamental qualities that make these cells so promising for regenerative medicine.…”

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confidence: 99%

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Stem Cells

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Serum-Free Medium Enhances the Immunosuppressive and Antifibrotic Abilities of Mesenchymal Stem Cells Utilized in Experimental Renal Fibrosis

Cited by 44 publications

References 58 publications

IFN-γ Enhances the Therapeutic Effect of Mscs on Experimental Renal Fibrosis

IFN-γ Enhances the Therapeutic Effect of Mscs on Experimental Renal Fibrosis

Mesenchymal stem cell-derived secretomes for therapeutic potential of premature infant diseases

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