Abstract WP88: In a Pro-inflammatory Environment, Mesenchymal Stromal Cells Exert Anti-inflammatory and Pro-angiogenic Effects on Endothelial Cells

Multipotent mesenchymal stromal cells (MSCs) have emerged as potent therapeutic agents for multiple indications. However, recent evidence indicates that MSC function is compromised in the physiological post-injury milieu. In this study, bone marrow (BM)- and adipose-derived (AD)-MSCs were preconditioned in hypoxia with or without inflammatory mediators to potentiate their immunotherapeutic function in preparation for in vivo delivery. Human MSCs were cultured for 48 h in either normoxia (21% O2) or hypoxia (2% O2) with or without the addition of Cytomix, thus creating 4 groups: (1) normoxia (21%); (2) Cytomix-normoxia (+21%); (3) hypoxia (2%); and (4) Cytomix-hypoxia (+2%). The 4 MSC groups were subjected to comprehensive evaluation of their characteristics and function. Preconditioning did not alter common MSC surface markers; nonetheless, Cytomix treatment triggered an increase in tissue factor (TF) expression. Moreover, the BM-MSCs and AD-MSCs from the +2% group were not able to differentiate to chondrocytes and osteoblasts, respectively. Following Cytomix preconditioning, the metabolism of MSCs was significantly increased while viability was decreased in AD-MSCs, but not in BM-MSCs. MSCs from both tissues showed a significant upregulation of key anti-inflammatory genes, increased secretion of IL-1 receptor antagonist (RA), and enhanced suppression of T-cell proliferation following the Cytomix treatment. Similarly, following a lipopolysaccharide challenge, the Cytomix-treated MSCs suppressed TNF-α secretion, while promoting the production of IL-10 and IL-1RA. These preconditioning approaches facilitate the production of MSCs with robust anti-inflammatory properties. AD-MSCs preconditioned with Cytomix under normoxia appear to be the most promising therapeutic candidates; however, safety concerns, such as thrombogenic disposition of cells due to TF expression, should be carefully considered prior to clinical translation.

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Adipose-derived mesenchymal stromal cells reverse high glucose–induced reduction of angiogenesis in human retinal microvascular endothelial cells

Cytotherapy ◽

10.1016/j.jcyt.2020.02.005 ◽

2020 ◽

Vol 22 (5) ◽

pp. 261-275 ◽

Cited By ~ 3

Author(s):

Agnese Fiori ◽

Hans-Peter Hammes ◽

Karen Bieback

Keyword(s):

Endothelial Cells ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

High Glucose ◽

Microvascular Endothelial Cells ◽

Microvascular Endothelial

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Placental Mesenchymal Stromal Cells (PMSCs) and PMSC-Derived Extracellular Vesicles (PMSC-EVs) Attenuated Renal Fibrosis in Rats with Unilateral Ureteral Obstruction (UUO) by Regulating CD4+ T Cell Polarization

Stem Cells International ◽

10.1155/2020/2685820 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Zhu Zhu ◽

Chaonan Han ◽

Shuli Xian ◽

Feng Zhuang ◽

Feng Ding ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Ureteral Obstruction ◽

Renal Fibrosis ◽

Unilateral Ureteral Obstruction ◽

Cell Infiltration ◽

Inflammatory Factors ◽

Anti Inflammatory

Purpose. Recent evidence has shown that CD4+ T helper (Th) cells are involved in renal inflammation and fibrosis. However, whether renal fibrosis can be alleviated by intervening in the polarization of CD4+ T cells remains unknown. Our research investigated the effects of intravenously administered placenta mesenchymal stromal cells (PMSCs) or treatment with extracellular EVs (EVs) derived from PMSCs (PMSC-EVs) on the polarization of CD4+ T cells in rats with unilateral ureteral obstruction (UUO). We further verified how PMSCs affect inflammatory factor secretion and the levels of regulatory T (Treg) and Th17 CD4+ T cells in vitro. Materials and Methods. We evaluated renal interstitial inflammation and fibrosis by pathological section staining, tested the polarization of CD4+ T cells (Th17 and Treg phenotypes) by flow cytometry (FCM) and immunohistochemistry, and detected the cytokines secreted by CD4+ T cells by enzyme-linked immunosorbent assay (ELISA). Results. Compared with that of control rats, the renal tissue of PMSC-treated rats exhibited lower renal Masson scores and more Foxp3+ cell infiltration, with a significantly decreased IL17A+CD4+ T cell/CD4+ T cell ratio and a significantly elevated anti-inflammatory cytokine (IL-10) level. When CD4+ T cells were cocultured with PMSCs, CD4+IL17A+ cell percentages were decreased in a UUO model after 7 days of coculture with PMSCs. The secretion of TGF-β and IL-10 was significantly increased (P<0.05), while the secretion of IFN-γ, IL-17, and IL-6 was significantly decreased (P<0.05) in the PMSC coculture group. Moreover, after treatment with PMSC-EVs, tubulointerstitial fibrosis was alleviated, and Foxp3+/IL-17+ cell infiltration was increased in the kidneys of UUO model animals on day 7. Conclusions. PMSCs can convert the inflammatory environment into an anti-inflammatory environment by affecting the polarization of CD4+ T cells and macrophages, inhibiting the inflammatory factors IFN-γ and IL-17, and upregulating the expression of the anti-inflammatory factors TGF-β and IL-10, ultimately leading to renal protection. Such functions may be mediated by the paracrine activity of PMSC-EVs.

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Human Amnion-Derived Mesenchymal Stromal Cells in Cirrhotic Patients with Refractory Ascites: A Possible Anti-Inflammatory Therapy for Preventing Spontaneous Bacterial Peritonitis

Stem Cell Reviews and Reports ◽

10.1007/s12015-020-10104-8 ◽

2021 ◽

Author(s):

Mariangela Pampalone ◽

Simona Corrao ◽

Giandomenico Amico ◽

Giampiero Vitale ◽

Rossella Alduino ◽

...

Keyword(s):

Ascitic Fluid ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Spontaneous Bacterial Peritonitis ◽

Refractory Ascites ◽

M2 Macrophage ◽

Human Amnion ◽

Bacterial Peritonitis ◽

Cirrhotic Patients ◽

Anti Inflammatory

AbstractCirrhosis is associated with dysregulated immune cell activation and immune dysfunction. These conditions modify gut flora, facilitate bacterial translocation, and increase susceptibility to bacterial peritonitis and consequent systemic infections by dramatically affecting long-term patient survival. Human amnion-derived mesenchymal stromal cells (hA-MSCs) exert immunomodulatory potential benefit, and have the ability to modulate their actions, especially in situations requiring immune activation through mechanisms not fully understood. In this study, we aimed to investigate, in vitro, the immunostimulant or immunosuppressive effects of hA-MSCs on cellular components of ascitic fluid obtained from cirrhotic patients with refractory ascites. We found that hA-MSCs viability is not affected by ascitic fluid and, interestingly, hA-MSCs diminished the pro-inflammatory cytokine production, and promoted anti-inflammatory M2 macrophage polarization. Moreover, we found that there was no simultaneous significant decrease in the M1-like component, allowing a continual phagocytosis activity of macrophages and NK cells to restore a physiological condition. These data highlight the plasticity of hA-MSCs’ immunomodulatory capacity, and pave the way to further understanding their role in conditions such as spontaneous bacterial peritonitis. Graphical abstract

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Fibrinolytic crosstalk with endothelial cells expands murine mesenchymal stromal cells

Blood ◽

10.1182/blood-2015-10-673103 ◽

2016 ◽

Vol 128 (8) ◽

pp. 1063-1075 ◽

Cited By ~ 13

Author(s):

Douaa Dhahri ◽

Kaori Sato-Kusubata ◽

Makiko Ohki-Koizumi ◽

Chiemi Nishida ◽

Yoshihiko Tashiro ◽

...

Keyword(s):

Bone Marrow ◽

Endothelial Cells ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Tyrosine Kinases ◽

Receptor Tyrosine Kinases ◽

Key Points ◽

Pharmacologic Inhibition

Key Points tPA expands mesenchymal stromal cells (MSCs) in the bone marrow by a cytokine (KitL and PDGF-BB) crosstalk with endothelial cells. Pharmacologic inhibition of receptor tyrosine kinases (c-Kit and PDGFRα) impairs tPA-mediated MSC proliferation.

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