Treatment of diabetic wounds with fetal murine mesenchymal stromal cells enhances wound closure

Badillo, Andrea; Redden, Robert A.; Zhang, Liping; Doolin, Edward J.; Liechty, Kenneth W.

doi:10.1007/s00441-007-0417-3

Cited by 104 publications

(105 citation statements)

References 39 publications

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“…The activity of the mTOR signaling pathway can be modulated by a variety of factors and pathways acting on different steps, and mTORC1 was activated by the binding of IGF1 to its receptor (40,43). After transplantation, ASCs remained viable at the injured site and secreted growth factors in a continuous and regulated manner in response to the environmental cues, including IGF (2,5,9,14,(22)(23)(24)37,44,46). We thus concluded that the increased muscle size, wet weight, and area of the myofibers in the ASC-transplanted groups are due to the following mechanism: The transplanted ASCs secrete growth factors; those stimulate the mTOR signaling pathway, which activates the synthesis of protein and muscle hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Effects of Mouse Adipose-Derived Stem Cells and Losartan in the Skeletal Muscle of Injured Mdx Mice

et al. 2015

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Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder caused by mutations in the dystrophin gene. Adipose-derived stem cells (ASCs) are an attractive source of cells for stem cell therapy. Losartan has been reported to improve ASC transplantation in injured mouse muscles. In the present study, we investigated whether the combined treatment of losartan and ASCs in the injured muscles of mdx mice improves regeneration. The combined treatment of ASCs and losartan remarkably improved muscle regeneration and induced muscle hypertrophy. In addition, ASCs and losartan treatment downregulated transforming growth factor-b and inhibited muscle fibrosis. We observed cells coexpressing green fluorescent protein (GFP) and dystrophin in the muscle samples of mice transplanted with GFP-positive ASCs. In the coculture in vitro experiment, we also observed that the GFP ASCs differentiated into dystrophin-expressing myotubes. The present study shows that the combination of transplanted ASCs and treatment with losartan ameliorated muscle fibrosis and improved muscle regeneration in injured mdx mice. Thus, we suggest that combined treatment with losartan and ASCs could help to improve muscle regeneration in the muscles of injured patients, including DMD patients.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Effects of Mouse Adipose-Derived Stem Cells and Losartan in the Skeletal Muscle of Injured Mdx Mice

et al. 2015

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“…However, they may cause excessive contraction by differentiating into myofibroblasts [39]. Moreover, direct vascular contribution of MSC is debated [40,41].…”

Section: Discussionmentioning

confidence: 99%

Integration of Blood Outgrowth Endothelial Cells in Dermal Fibroblast Sheets Promotes Full Thickness Wound Healing

et al. 2010

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Vascularization is the cornerstone of wound healing. We introduced human blood outgrowth endothelial cells (hBOEC) in a self-assembled human dermal fibroblast sheet (hDFS), intended as a tissue-engineered dermal substitute with inherent vascular potential. hBOEC were functionally and molecularly different from early endothelial progenitor cells and human umbilical vein endothelial cells (HUVEC). hBOEC alone, unlike HUVEC, efficiently revascularized and re-oxygenated the wound bed, both by active incorporation into new vessels and by trophic stimulation of host angiogenesis in a dose-dependent manner. Furthermore, hBOEC alone, but not HUVEC, accelerated epithelial coverage and matrix organization of the wound bed. In addition, integration of hBOEC in hDFS not only further improved vascularization, epithelial coverage and matrix organization but also prevented excessive wound contraction. In vitro analyses with hBOEC, fibroblasts and keratinocytes revealed that these effects were both due to growth factor crosstalk and to short cutting hypoxia. Among multiple growth factors secreted by hBOEC, placental growth factor mediated at least in part the beneficial effects on keratinocyte migration and proliferation. Overall, this combined tissue engineering approach paves the way for clinical development of a fully autologous vascularized dermal substitute for patients with large skin defects that do not heal properly.

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“…3 Decreased angiogenesis, 4 impaired growth factor production, 5 an altered inflammatory and immune response, 5 a decreased rate of wound contraction, 6 and an imbalance between the accumulation of extracellular components and their remodeling by matrix metalloproteinases (MMPs) 7,8 have all been demonstrated in diabetic wounds. MMP-2 and MMP-9 have been shown to be present in greater concentration in wounded diabetic animals than their nondiabetic littermates, which is similar to findings from patients with nonhealing ulcers.…”

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confidence: 99%

Impaired Biomechanical Properties of Diabetic Skin

Bermudez

Herdrich

et al. 2011

The American Journal of Pathology

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106

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Diabetic skin is known to have deficient wound healing properties, but little is known of its intrinsic biomechanical properties. We hypothesize that diabetic skin possesses inferior biomechanical properties at baseline, rendering it more prone to injury. Skin from diabetic and nondiabetic mice and humans underwent biomechanical testing. Real-time PCR was performed for genes integral to collagen synthesis and degradation. MMP-2 and MMP-9, and TIMP-1 protein levels were assessed by ELISA and zymography. Collagen I and III content was assessed using Western blot analysis. At baseline, both murine and human diabetic skin was biomechanically inferior compared to nondiabetic skin, with decreased maximum stress and decreased modulus (P < 0.001 and < 0.05, respectively). Surprisingly, the expression of genes involved in collagen synthesis were significantly up-regulated, and genes involved in collagen degradation were significantly down-regulated in murine diabetic skin (P < 0.01). In addition, MMP-2 and MMP-9/TIMP-1 protein ratios were significantly lower in murine diabetic skin (P < 0.05). Collagen I levels and I:III ratios were lower in diabetic skin (P < 0.05). These findings suggest that the predisposition of diabetics to wounds may be the result of impaired tissue integrity at baseline, and are due, in part, to a defect in the regulation of collagen protein synthesis at the post-transcriptional level. Diabetes is associated with increased morbidity and mortality, 1 as well as impaired wound healing. 2 Diabetesrelated admissions accounted for 22% of all hospital inpatient days in 2007, and diabetic foot ulcers account for 20% of all hospital admissions in diabetic patients, which are the leading cause of lower extremity amputations. 2 Improvements made in diabetic wound management and prevention clearly have the potential to affect a large number of patients and decrease diabetic-related health care expenditures.More than 100 factors have been identified that contribute to the impairment in diabetic wound healing. 3 Decreased angiogenesis, 4 impaired growth factor production, 5 an altered inflammatory and immune response, 5 a decreased rate of wound contraction, 6 and an imbalance between the accumulation of extracellular components and their remodeling by matrix metalloproteinases (MMPs) 7,8 have all been demonstrated in diabetic wounds. MMP-2 and MMP-9 have been shown to be present in greater concentration in wounded diabetic animals than their nondiabetic littermates, which is similar to findings from patients with nonhealing ulcers. 9 Diabetes is characterized by significantly increased cross linking and nonenzymatic glycation of collagen, as well as elevated levels of advanced glycation end products (AGEs). 10,11 Blockade of the receptor for advanced glycation end products (RAGEs) can restore the wound healing properties of diabetic (Db/Db) mice. 12 Hyperglycemic animals have been shown to have significantly higher concentrations of glycated collagen and higher levels of collagenase activity. 9,13 Furthermore...

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Treatment of diabetic wounds with fetal murine mesenchymal stromal cells enhances wound closure

Cited by 104 publications

References 39 publications

Therapeutic Effects of Mouse Adipose-Derived Stem Cells and Losartan in the Skeletal Muscle of Injured Mdx Mice

Therapeutic Effects of Mouse Adipose-Derived Stem Cells and Losartan in the Skeletal Muscle of Injured Mdx Mice

Integration of Blood Outgrowth Endothelial Cells in Dermal Fibroblast Sheets Promotes Full Thickness Wound Healing

Impaired Biomechanical Properties of Diabetic Skin

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