Activated mesenchymal stem cells increase wound tensile strength in aged mouse model via macrophages

Lee, Simon; Szilàgyi, Erzsèbet; Chen, Lin; Premanand, Kavitha; DiPietro, Luisa A.; Ennis, William J.; Bartholomew, Amelia

doi:10.1016/j.jss.2012.05.040

Cited by 38 publications

(22 citation statements)

References 21 publications

(13 reference statements)

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“…We determined the role of skin-wound M⌽s in NPD1 biosynthesis by treating mice with chlondrate liposomes. Following clodronate-liposome treatment, besides slightly reduced activity, mice continued consuming food and water normally and showed no obvious illness or weight loss, consistent with previous reports using similar procedures and doses of CL (23,40). M⌽-depletion by CL treatment reduced F4/80 ϩ M⌽s by 78% in the skin wounds of db/db mice at day 7 postwounding based on immunohistological analysis of F4/80 ϩ M⌽s in the skin wound sections (Fig.…”

Section: Resultssupporting

confidence: 88%

“…M⌽s were depleted in mice by administration of dichloromethylene-diphosphonate (Clodronate)-loaded liposomes (CL) (Encapsula Nano-Sciences, Nashville, TN) following the established procedures for similar animal conditions (23,40,74). CL was injected at 51 mg/kg ip (200 l/mouse) and subcutaneously at 50 l/wound (in RPMI 1640 as above or site to be wounded), 5 days before wounding and then every 3 days until the mice were killed at 7 dpw.…”

Section: Methodsmentioning

confidence: 99%

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Neuroprotectin/protectin D1: endogenous biosynthesis and actions on diabetic macrophages in promoting wound healing and innervation impaired by diabetes

Hong

Tian

Lü

et al. 2014

American Journal of Physiology-Cell Physiology

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Dysfunction of macrophages (MΦs) in diabetic wounds impairs the healing. MΦs produce anti-inflammatory and pro-resolving neuroprotectin/protectin D1 (NPD1/PD1, 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid); however, little is known about endogenous NPD1 biosynthesis by MΦs and the actions of NPD1 on diabetic MΦ functions in diabetic wound healing. We used an excisional skin wound model of diabetic mice, MΦ depletion, MΦs isolated from diabetic mice, and mass spectrometry-based targeted lipidomics to study the time course progression of NPD1 levels in wounds, the roles of MΦs in NPD1 biosynthesis, and NPD1 action on diabetic MΦ inflammatory activities. We also investigated the healing, innervation, chronic inflammation, and oxidative stress in diabetic wounds treated with NPD1 or NPD1-modulated MΦs from diabetic mice. Injury induced endogenous NPD1 biosynthesis in wounds, but diabetes impeded NPD1 formation. NPD1 was mainly produced by MΦs. NPD1 enhanced wound healing and innervation in diabetic mice and promoted MΦs functions that accelerated these processes. The underlying mechanisms for these actions of NPD1 or NPD1-modulated MΦs involved 1) attenuating MΦ inflammatory activities and chronic inflammation and oxidative stress after acute inflammation in diabetic wound, and 2) increasing MΦ production of IL10 and hepatocyte growth factor. Taken together, NPD1 appears to be a MΦs-produced factor that accelerates diabetic wound healing and promotes MΦ pro-healing functions in diabetic wounds. Decreased NPD1 production in diabetic wound is associated with impaired healing. This study identifies a new molecular target that might be useful in development of more effective therapeutics based on NPD1 and syngeneic diabetic MΦs for treatment of diabetic wounds.

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Section: Resultssupporting

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Neuroprotectin/protectin D1: endogenous biosynthesis and actions on diabetic macrophages in promoting wound healing and innervation impaired by diabetes

Hong

Tian

Lü

et al. 2014

American Journal of Physiology-Cell Physiology

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“…(9) Previous studies have reported that MSCs activated by the pro-inflammatory cytokine interferon gamma (IFN-γ) are able to increase wound regeneration and tensile strength that is correlated with the amount of collagen. (13) On the other hand, MSCs that are activated in vitro by TNF-α, lipopolysaccharide (LPS) and hypoxia, are able to increase the production of growth factors, particularly VEGF, (14) but the role of TNF-α-activated MSCs on VEGF concentrations and their relationship with collagen are as yet unknown. The aim of the present study was to evaluate the effect of MSCs that are activated by TNF-α at a dose of 10 ng/ml on VEGF and collagen concentrations in rats with incised wounds.…”

Section: Introductionmentioning

confidence: 99%

Tumor necrosis factor-α-activated mesenchymal stem cells accelerate wound healing through vascular endothelial growth factor regulation in rats

Nugraha

Putra

2018

Universa Medicina

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Background Wounds are areas of physical or thermal damage of the epithelial layer of skin or mucosa. The wound healing process consists of hemostasis, inflammation, proliferation, and remodeling. Mesenchymal stem cells (MSCs) play a role in wound healing by suppressing potent pro-inflammatory molecules, such as tumor necrosis factor-α (TNF-α), leading to macrophage polarization from the pro-inflammatory type to the pro-regeneration type characterized by increasing vascular endothelial growth factor (VEGF) production. MSCs are able to increase VEGF level in-vivo correlated with collagen synthesis. The objective of this study was to assess the role of TNF-α-activated MSCs on VEGF in rat wounds. Methods An experimental animal study with post-test only control group design was performed involving 24 Wistar rats. The rats were randomized into four groups consisting of one control (K) and three treatment groups (P) (activated MSCs at doses of 3x105, 6x105, and 12x105 cells, respectively). The measurement of VEGF levels was done using ELISA assay while the collagen analysis was performed by light microscopy. One way ANOVA and Post Hoc LSD were used to analyze the data. Results The results showed a significant increase in VEGF levels (p <0.05) on day 3 and then a significant decrease on day 5 along with a significant increase in the amount of collagen on day 7 (p<0.05). Conclusion This study demonstrated that TNF-α-activated MSCs were able to regulate VEGF levels and collagen synthesis in wound healing in rats. The molecular mechanism by which TNF-α-activated MSCs stimulate cutaneous wound healing should be clarified further.

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“…One of the approaches is the preactivation or licensing of MSCs with cytokines, such as IFN- γ , IL-1 β , and TNF- α [19, 20], creating a proinflammatory environment to stimulate MSC immunosuppressive properties [20]. IFN- γ -stimulated MSCs shave increased immunosuppressive capabilities [21] and are more efficient in the prevention of colitis [22], graft-versus-host disease (GVHD) [23, 24], and autoimmune encephalomyelitis [25] and in wound healing [26] compared to untreated cells.…”

Section: Introductionmentioning

confidence: 99%

In Vivo Immunogenic Response to Allogeneic Mesenchymal Stem Cells and the Role of Preactivated Mesenchymal Stem Cells Cotransplanted with Allogeneic Islets

Oliveira

Chagastelles

Sesterheim

et al. 2017

Stem Cells International

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Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into cells from the mesenchymal lineage. The hypoimmunogenic characteristic of MSCs has encouraged studies using allogeneic MSCs for the treatment of autoimmune diseases and inflammatory conditions. Promising preclinical results and the safety of allogeneic MSC transplantation have created the possibility of “off-the-shelf” clinical application of allogeneic cells. This study has aimed to evaluate the survival of untreated and IFN-γ- and TNF-α-treated (preactivated) allogeneic MSCs transplanted under the kidney capsule of immunocompetent mice together with the role of preactivated MSCs after cotransplantation with allogeneic islets. The preactivation of MSCs upregulated the gene expression of anti-inflammatory molecules and also enhanced their immunomodulatory capacity in vitro. In vivo, allogeneic MSCs provoked an immunogenic response, with the infiltration of inflammatory cells at the transplant site and full graft rejection in both the untreated and preactivated groups. Allogeneic islets cotransplanted with preactivated MSCs prolonged graft survival for about 6 days, compared with islet alone. The present results corroborate the hypothesis that allogeneic MSCs are not immune-privileged and that after playing their therapeutic role they are rejected. Strategies that reduce allogeneic MSC immunogenicity can potentially prolong their in vivo persistence and improve the therapeutic effects.

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Activated mesenchymal stem cells increase wound tensile strength in aged mouse model via macrophages

Cited by 38 publications

References 21 publications

Neuroprotectin/protectin D1: endogenous biosynthesis and actions on diabetic macrophages in promoting wound healing and innervation impaired by diabetes

Neuroprotectin/protectin D1: endogenous biosynthesis and actions on diabetic macrophages in promoting wound healing and innervation impaired by diabetes

Tumor necrosis factor-α-activated mesenchymal stem cells accelerate wound healing through vascular endothelial growth factor regulation in rats

In Vivo Immunogenic Response to Allogeneic Mesenchymal Stem Cells and the Role of Preactivated Mesenchymal Stem Cells Cotransplanted with Allogeneic Islets

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