Transforming Growth Factor-β1 Fails to Stimulate Wound Healing and Impairs Its Signal Transduction in an Aged Ischemic Ulcer Model

Wu, Liancun; Xia, Yifan; Roth, Sanford I.; Gruskin, Elliott; Mustoe, Thomas A.

doi:10.1016/s0002-9440(10)65276-5

Cited by 104 publications

(94 citation statements)

References 54 publications

(61 reference statements)

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“…Yet, numerous clinical studies of recombinant growth factors used to treat chronic wounds have reported disappointing results [68]. Proteolytic degradation of growth factors and unresponsive growth factor signaling cascades are thought to contribute to an impaired wound healing response [69,70]. Interestingly, consistent with those results, we found that cellular proliferation, migration, and angiogenesis were significantly impaired when the conditioned medium was depleted of exosomes by ultracentrifugation.…”

Section: Discussionsupporting

confidence: 84%

Mesenchymal Stem Cell Exosomes Induce Proliferation and Migration of Normal and Chronic Wound Fibroblasts, and Enhance Angiogenesis In Vitro

Shabbir

Cox

Rodriguez-Menocal

et al. 2015

Stem Cells and Development

563

480

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Although chronic wounds are common and continue to be a major cause of morbidity and mortality, treatments for these conditions are lacking and often ineffective. A large body of evidence exists demonstrating the therapeutic potential of mesenchymal stem cells (MSCs) for repair and regeneration of damaged tissue, including acceleration of cutaneous wound healing. However, the exact mechanisms of wound healing mediated by MSCs are unclear. In this study, we examined the role of MSC exosomes in wound healing. We found that MSC exosomes ranged from 30 to 100-nm in diameter and internalization of MSC exosomes resulted in a dosedependent enhancement of proliferation and migration of fibroblasts derived from normal donors and chronic wound patients. Uptake of MSC exosomes by human umbilical vein endothelial cells also resulted in dosedependent increases of tube formation by endothelial cells. MSC exosomes were found to activate several signaling pathways important in wound healing (Akt, ERK, and STAT3) and induce the expression of a number of growth factors [hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF1), nerve growth factor (NGF), and stromal-derived growth factor-1 (SDF1)]. These findings represent a promising opportunity to gain insight into how MSCs may mediate wound healing.

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Section: Discussionsupporting

confidence: 84%

Mesenchymal Stem Cell Exosomes Induce Proliferation and Migration of Normal and Chronic Wound Fibroblasts, and Enhance Angiogenesis In Vitro

Shabbir

Cox

Rodriguez-Menocal

et al. 2015

Stem Cells and Development

563

480

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“…(TGF-␤1 is increased more in the early phases of wound healing, which are prolonged in ischemic ears). In contrast, rabbit ear ulcers in aged animals failed to show any significant increase in TGF-␤1 mRNA under ischemic and nonischemic conditions until day 12, a finding consistent with the greater delay in wound healing in the aged animals [3]. Further research into the signaling pathway of TGF-␤ showed that aged human dermal fibroblasts have altered TGF-␤ signal transduction because of downregulated receptors.…”

Section: Hypoxia and Tgf-␤-1mentioning

confidence: 58%

“…The aged have an altered response to hypoxia, and wound healing is markedly delayed. The ischemic rabbit ear model evidences such delay in aged animals, and the depression was shown to be evident even in middle-aged rabbits [3]. By maintaining chronic ischemia in the rabbit ear model, a chronic wound model can beproduced in which there is minimal healing, even after 26 days [32].…”

Section: Impact Of Aging On Hypoxic Stimulusmentioning

confidence: 98%

“…Tissue oxygen tensions from 5 to 20 mmHg were measured transcutanously in nonhealing chronic wounds compared to control tissue values of 30-50 mmHg [2]. Under controlled experimental conditions in vivo, we were able to show in young and aged ischemic rabbit ear ulcers that wound healing is delayed under hypoxia as a result of reduced granulation tissue production and delayed epithelialization [3,4]. Ischemic ears in this rabbit ear model have tissue oxygen tensions of approximately 24 mmHg versus the level of 53 mmHg measured in non-ischemic ears [5].…”

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confidence: 99%

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Oxygen in wound healing: More than a nutrient

Davidson

Mustoe

2001

Wound Repair Regeneration

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Abstract. This article provides an overview of the role of oxygen in wound healing. The understanding of this role has undergone a major evolution from its long-recognized importance as an essential factor for oxidative metabolism, to its recognition as an important cell signal interacting with growth factors and other signals to regulate signal transduction pathways. Our laboratory has been engaged in thestudy of animal models of skin ischemia to explore in vivo the impact of hypoxia as well as the use of oxygen as a therapeutic agent either alone or in combination with other agents such as growth factors. We have demonstrated a synergistic effect of systemic hyperbaric oxygen and growth factors that has been substantiated by Hunt's group. Within the past 10 years research in the field of wound healing has given new insight into the mechanism of action of hypoxia and hyperoxia as modifiers of the normal time-course of wound healing. The article concludes with a discussion of why hypoxia and hyperoxia intercurrently play an important role in wound healing. Hypoxia-inducible factor 1 is crucial in that interplay.

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“…This likely reflects a reduction in the number of capillaries as well as a reduction in mitochondrial enzyme activity 68 . Animal models (rabbit 69 and mouse 69,70 ) have suggested that aging and ischemia have an additive effect on disruption of wound healing. Consequently, the potential benefit of increasing tissue oxygen tension during surgical wound repair in older patients should be further evaluated.…”

mentioning

confidence: 99%

Anesthesia, Microcirculation, and Wound Repair in Aging

Bentov¹,

Reed²

2014

Survey of Anesthesiology

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Age related changes in skin contribute to impaired wound healing after surgical procedures. Changes in skin with age include decline in thickness and composition, a decrease in the number of most cell types and diminished microcirculation. The microcirculation provides tissue perfusion, fluid homeostasis, and delivery of oxygen and other nutrients. It also controls temperature and the inflammatory response. Surgical incisions cause further disruption of the microvasculature of aged skin. Perioperative management can be modified to minimize insults to aged tissues. Judicious use of fluids, maintenance of normal body temperature, pain control and increased tissue oxygen tension are examples of adjustable variables that support the microcirculation. Anesthetic agents influence the microcirculation from a combination of effects on cardiac output, arterial pressure and local micro-vascular changes. We examine the role of anesthetic management in optimizing the microcirculation and potentially improving postoperative wound repair in older persons. I. BackgroundSurgical wound repair is a major problem in the older population 1 , who are at increased risk of wound dehiscence and infection 2 . As a specific example, surgical site infections (SSI) are common (about 500,000 cases annually in the United States), lead to worse patient outcome (patients who develop SSI are twice as likely to die 3 ), and are an enormous economic burden (1-10 billion dollars annually) 4 . Many factors contribute to age related changes in skin 5 and subsequent vulnerability to impaired wound healing and infection. Changes in skin with age ( Figure 1) include a decline in epidermal and dermal thickness and composition, as well as a decrease in the number of most resident cell types. The dermalepidermal junction is flattened and the microcirculation is diminished 6 . The latter is defined as blood flow through arterioles, capillaries and venules and is the key system that affects the entire skin surface. In the aging patient, the skin's microcirculation is reduced by 40% between the ages of 20 to 70 years 7 . The microcirculation provides tissue perfusion, fluid hemostasis, and delivery of oxygen and other nutrients. It also controls temperature and the inflammatory response. Surgical incisions cause disruption of the skin's microcirculation as manifested by local edema resulting from vasodilation and increased vascular permeability. Summary StatementAged skin is at increased risk of poor post-operative wound healing. Changes in the cutaneous microcirculation with aging contribute to this risk. This review examines the role of anesthesia management on microcirculatory function. In this review, we will use skin as a representative organ to describe age-related changes that negatively affect the microcirculation and have subsequent impacts on wound healing and the incidence of postoperative infection. We will then examine the role of anesthesia management in minimizing detrimental effects on the microcirculation. A greater understanding of...

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Transforming Growth Factor-β1 Fails to Stimulate Wound Healing and Impairs Its Signal Transduction in an Aged Ischemic Ulcer Model

Cited by 104 publications

References 54 publications

Mesenchymal Stem Cell Exosomes Induce Proliferation and Migration of Normal and Chronic Wound Fibroblasts, and Enhance Angiogenesis In Vitro

Mesenchymal Stem Cell Exosomes Induce Proliferation and Migration of Normal and Chronic Wound Fibroblasts, and Enhance Angiogenesis In Vitro

Oxygen in wound healing: More than a nutrient

Anesthesia, Microcirculation, and Wound Repair in Aging

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