Ex Vivo Activated Human Macrophages Improve Healing, Remodeling, and Function of the Infarcted Heart

Leor, Jonathan; Rozen, Liat; Zuloff-Shani, Adi; Feinberg, Micha S.; Amsalem, Yoram; Barbash, Israel M.; Kachel, Erez; Holbová, Radka; Mardor, Yael; Daniels, Dianne; Ocherashvilli, Aharon; Orenstein, Arie; Danon, D.

doi:10.1161/circulationaha.105.000331

Cited by 130 publications

(112 citation statements)

References 26 publications

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“…Timely recruitment of macrophages is necessary for wound healing (24,25). In the nonischemic wounds, macrophage recruitment was markedly compromised, consistent with our observation in the preclinical setting (4).…”

Section: Discussionsupporting

confidence: 87%

Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds

Biswas¹,

Roy²,

Banerjee³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

249

199

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Ischemia complicates wound closure. Here, we are unique in presenting a murine ischemic wound model that is based on bipedicle flap approach. Using this model of ischemic wounds we have sought to elucidate how microRNAs may be implicated in limiting wound reepithelialization under hypoxia, a major component of ischemia. Ischemia, evaluated by laser Doppler as well as hyperspectral imaging, limited blood flow and lowered tissue oxygen saturation. EPR oximetry demonstrated that the ischemic wound tissue had pO 2 <10 mm Hg. Ischemic wounds suffered from compromised macrophage recruitment and delayed wound epithelialization. Specifically, epithelial proliferation, as determined by Ki67 staining, was compromised. In vivo imaging showed massive hypoxia inducible factor-1α (HIF-1α) stabilization in ischemic wounds, where HIF-1α induced miR-210 expression that, in turn, silenced its target E2F3, which was markedly down-regulated in the wound-edge tissue of ischemic wounds. E2F3 was recognized as a key facilitator of cell proliferation. In keratinocytes, knock-down of E2F3 limited cell proliferation. Forced stabilization of HIF-1α using Ad-VP16-HIF-1α under normoxic conditions upregulated miR-210 expression, down-regulated E2F3, and limited cell proliferation. Studies using cellular delivery of miR-210 antagomir and mimic demonstrated a key role of miR-210 in limiting keratinocyte proliferation. In summary, these results are unique in presenting evidence demonstrating that the hypoxia component of ischemia may limit wound re-epithelialization by stabilizing HIF-1α, which induces miR-210 expression, resulting in the down-regulation of the cell-cycle regulatory protein E2F3.skin | tissue repair | wound healing

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Section: Discussionsupporting

confidence: 87%

Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds

Biswas¹,

Roy²,

Banerjee³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

249

199

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“…Adult cutaneous tissue repair is accompanied by a robust recruitment of inflammatory cells to the wound site (46). Timely recruitment of macrophages is necessary for wound healing (34,39). In the nonischemic wounds, macrophage recruitment was rapid, peaking on day 3 and subsiding on day 7 postwounding.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a preclinical model of chronic ischemic wound

Roy

Biswas

Khanna

et al. 2009

Physiological Genomics

111

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Chronic ischemic wounds presenting at wound clinics are heterogeneous with respect to etiology, age of the wound, and other factors complicating wound healing. In addition, there are ethical challenges associated with collecting repeated biopsies from a patient to develop an understanding of the temporal dynamics of the mechanisms underlying chronic wounds. The need for a preclinical model of ischemic wound is therefore compelling. The porcine model is widely accepted as an excellent preclinical model for human wounds. A full-thickness bipedicle flap approach was adopted to cause skin ischemia. Closure of excisional wounds placed on ischemic tissue was severely impaired resulting in chronic wounds. Histologically, ischemic wounds suffered from impaired re-epithelialization, delayed macrophage recruitment and poorer endothelial cell abundance and organization. Compared with the pair-matched nonischemic wound, unique aspects of the ischemic wound biology were examined on days 3, 7, 14, and 28 by systematic screening of the wound tissue transcriptome using high-density porcine GeneChips. Ischemia markedly potentiated the expression of arginase-1, a cytosolic enzyme that metabolizes the precursor of nitric oxide l-arginine. Ischemia also induced the SOD2 in the wound tissue perhaps as survival response of the challenged tissue. Human chronic wounds also demonstrated elevated expression of SOD2 and arginase-1. This study provides a thorough database that may serve as a valuable reference tool to develop novel hypotheses aiming to elucidate the biology of ischemic chronic wounds in a preclinical setting.

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“…44 On the other hand, in the control group that was treated with the standard of care, only 41.3% (31 out of 75 ulcers) achieved 50% area closure in 26 to 368 days. 44 Leor et al 45 studied the impact of directly injecting macrophages to ischemic myocardial tissue in a rat model. Human macrophages were isolated from peripheral blood, activated in vitro by a novel method based on hypoosmotic shock, and directly injected into the ischemic cardiac tissue 1 min after the induction of myocardial infarction.…”

Section: Delivery Of Macrophages As a Cellular Therapy For Tissue Repairmentioning

confidence: 99%

Drug delivery strategies to control macrophages for tissue repair and regeneration

Garash

Bajpai

Marcinkiewicz

et al. 2016

Exp Biol Med (Maywood)

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Tissue repair and regeneration is a complex process. Our bodies have an excellent capacity to regenerate damaged tissues in many situations. However, tissue healing is impaired in injuries that exceed a critical size or are exacerbated by chronic inflammatory diseases like diabetes. In these instances, biomaterials and drug delivery strategies are often required to facilitate tissue regeneration by providing physical and biochemical cues. Inflammation is the body's response to injury. It is critical for wound healing and biomaterial integration and vascularization, as long as the timing is well controlled. For example, chronic inflammation is well known to impair healing in chronic wounds. In this review, we highlight the importance of a well-controlled inflammatory response, primarily mediated by macrophages in tissue repair and regeneration and discuss various strategies designed to promote regeneration by controlling macrophage behavior. These strategies include temporally controlled delivery of anti-inflammatory drugs, delivery of macrophages as cellular therapy, controlled release of cytokines that modulate macrophage phenotype, and the design of nanoparticles that exploit the inherent phagocytic behavior of macrophages. A clear outcome of this review is that a deeper understanding of the role and timing of complex macrophage phenotypes or activation states is required to fully harness their abilities with drug delivery strategies.

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Ex Vivo Activated Human Macrophages Improve Healing, Remodeling, and Function of the Infarcted Heart

Cited by 130 publications

References 26 publications

Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds

Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds

Characterization of a preclinical model of chronic ischemic wound

Drug delivery strategies to control macrophages for tissue repair and regeneration

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