Antigen-Mediated, Macrophage-Stimulated, Accelerated Wound Healing Using α-Gal Nanoparticles

Kaymakcalan, Omer; Karinja, Sarah J.; Abadeer, Andrew I.; Dong, Xue; Jin, Julia; Galili, Uri; Spector, Jason A.

doi:10.1097/sap.0000000000001360

Cited by 14 publications

(16 citation statements)

References 34 publications

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“…We have previously reported that extensive immune mediated complement activation which results in macrophage recruitment, is associated with accelerated regeneration and prevention of fibrosis in skin injuries of adult mice treated with αgal nanoparticles (24)(25)(26)(27)(28)(29). These nanoparticles present a carbohydrate antigen, called the "α-gal epitope, " with the structure Galα1-3Galβ1-4GlcNAc-R (25,27).…”

Section: Introductionmentioning

confidence: 99%

“…Since anti-Gal is present in all humans and anti-Gal/α-gal immune complexes effectively activate the complement system, we hypothesized that formation of such immune complexes in the form of anti-Gal interaction with α-gal nanoparticles may be considered as a platform for future induction of a variety of regenerative therapies (30). The previous studies on skin injury repair and regeneration (24)(25)(26)(27)(28)(29) indicated that anti-Gal/α-gal nanoparticles interaction at the administration site of these nanoparticles, activates the complement system to generate large amounts of C5a and C3a complement cleavage peptides that induce recruitment of multiple macrophages into the treated injuries. The recruited macrophages bind via their Fc receptors the Fc "tail" of anti-Gal immunocomplexed with the multiple α-gal epitopes on the nanoparticles and are activated to polarize into pro-reparative macrophages that secrete a variety of cytokines which decrease the healing time by ∼50% and prevent fibrosis and scar formation.…”

Section: Introductionmentioning

confidence: 99%

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Near Complete Repair After Myocardial Infarction in Adult Mice by Altering the Inflammatory Response With Intramyocardial Injection of α-Gal Nanoparticles

Galili

Zhu

Chen

et al. 2021

Front. Cardiovasc. Med.

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Background: Neonatal mice, but not older mice, can regenerate their hearts after myocardial-infarction (MI), a process mediated by pro-reparative macrophages. α-Gal nanoparticles applied to skin wounds in adult-mice bind the anti-Gal antibody, activate the complement cascade and generate complement chemotactic peptides that recruit pro-reparative macrophages which are further activated by these nanoparticles. The recruited macrophages decrease wound healing time by ~50%, restore the normal skin structure and prevent fibrosis and scar formation in mice.Objectives: The objective of this study is to determine if α-gal nanoparticles injected into the reperfused myocardium after MI in adult-mice can induce myocardial repair that restores normal structure, similar to that observed in skin injuries.Methods and Results: MI was induced by occluding the mid-portion of the left anterior descending (LAD) coronary artery for 30 min. Immediately following reperfusion, each mouse received two 10 μl injections of 100 μg α-gal nanoparticles in saline into the LAD territory (n = 20), or saline for controls (n = 10). Myocardial infarct size was measured by planimetry following Trichrome staining and macrophage recruitment by hematoxylin-eosin staining. Left ventricular (LV) function was measured by echocardiography. Control mice displayed peak macrophage infiltration at 4-days, whereas treated mice had a delayed peak macrophage infiltration at 7-days. At 28-days, control mice demonstrated large transmural infarcts with extensive scar formation and poor contractile function. In contrast, mice treated with α-gal nanoparticles demonstrated after 28-days a marked reduction in infarct size (~10-fold smaller), restoration of normal myocardium structure and contractile function.Conclusions: Intramyocardial injection of α-gal nanoparticles post-MI in anti-Gal producing adult-mice results in near complete repair of the infarcted territory, with restoration of normal LV structure and contractile function. The mechanism responsible for this benefit likely involves alteration of the usual inflammatory response post-MI, as previously observed with regeneration of injured hearts in adult zebrafish, salamanders and neonatal mice.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Near Complete Repair After Myocardial Infarction in Adult Mice by Altering the Inflammatory Response With Intramyocardial Injection of α-Gal Nanoparticles

Galili

Zhu

Chen

et al. 2021

Front. Cardiovasc. Med.

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“…It follows then that topical AGNs might be utilized to modulate local inflammation through macrophage activation, which has great implications for enhancement of wound healing. AGN application in mice and pig wound models have demonstrated rapid recruitment of macrophages and induction of polarization of the recruited macrophages toward the M2, pro-healing lineage [12][13][14][15][16][17]35].…”

Section: Discussionmentioning

confidence: 99%

“…These submicroscopic liposomes can present as many as 10 15 epitopes per 1 mg of AGNs [14]. It has been shown that topical application of AGNs in anti-Gal producing mice leads to recruitment and activation of macrophages resulting in release of multiple growth factors and cytokines including VEGF, FGF-1, FGF-2, PDGF-A, PDGF-B, CSF-1, and CSF-2 [14,15] which in turn stimulate and activate downstream cellular mechanisms involved in wound healing such as fibroblast activation and collagen deposition. Additionally, improved collagen deposition and epithelial migration has been observed in AGN-treated murine and porcine models of normal wound and burn healing [13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Topical α-Gal Nanoparticles Enhance Wound Healing in Radiated Skin

Samadi

Buro

Dong

et al. 2021

Skin Pharmacol Physiol

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Surgery within radiated tissue is associated with increased complication rates. It is hypothesized that impaired wound healing may result from aberrant inflammatory responses that occur in previously radiated tissues. Previous work has demonstrated that the topical application of naturally occurring antigen α-gal (Galα1-3Galβ1-(3)4GlcNAc-R) nanoparticles (AGNs) within wounds accelerates macrophage recruitment and subsequent healing in both normal and diabetic wounds. Herein, we hypothesize that application of this antigen would similarly enhance wound healing in irradiated tissues. Methods: To simulate human physiology, α-1,3-galactosyltransferase knockout (KO) mice were exposed to the antigen to produce anti-α-gal antibodies (anti-Gal). Ten days prior to wounding, the dorsal skin was irradiated with 1 session of 40 Gy. Bilateral dorsal 6-mm splinted full-thickness wounds were created within the radiated skin and treated with 50 µL of AGNs (50 mg/mL) immediately after wounding and again on postoperative day 1. A control KO group underwent similar irradiation and wounding protocols but was treated with phosphate-buffered saline (PBS) vehicle. Wild-type (WT) mice, which do not produce anti-Gal, went through the same irradiation and wounding. Results: Histologic analysis demonstrated enhanced epithelial migration in the radiated/AGN-treated KO wounds, which was significantly elevated in comparison to radiated/PBS-treated KO wounds beginning by day 15 and continuing until the end of the study (p < 0.01). In WT mice, treatment with AGNs showed no effect on epithelial migration. Conclusions: Topical application of AGNs onto irradiated wounds significantly ameliorates the delayed wound healing classically seen in radiated skin and results in faster wound closure with only transient application.

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“…Wound and burn healing by α-gal nanoparticles —the effects of α-gal therapy by α-gal nanoparticles were studied on skin injuries ( Galili et al, 2010 ; Wigglesworth et al, 2011 ; Kaymakcalan et al, 2020 ; Galili, 2017 ; Kaymakcalan et al, 2018 ; Samadi et al, 2021 ; Hurwitz et al, 2012 ). Application of α-gal nanoparticles to full-thickness wounds or burns of anti-Gal–producing GT-KO mice decreased the healing time by ∼50% in comparison to wound healing time in untreated GT-KO mice.…”

Section: Immunological Processes Associated With Anti-gal/α-gal Epitope Interactions Which May Be Harnessed For α-Gal Therapiesmentioning

confidence: 99%

Biosynthesis of α-Gal Epitopes (Galα1-3Galβ1-4GlcNAc-R) and Their Unique Potential in Future α-Gal Therapies

Galili

2021

Front. Mol. Biosci.

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The α-gal epitope is a carbohydrate antigen which appeared early in mammalian evolution and is synthesized in large amounts by the glycosylation enzyme α1,3galactosyltransferase (α1,3GT) in non-primate mammals, lemurs, and New-World monkeys. Ancestral Old-World monkeys and apes synthesizing α-gal epitopes underwent complete extinction 20–30 million years ago, and their mutated progeny lacking α-gal epitopes survived. Humans, apes, and Old-World monkeys which evolved from the surviving progeny lack α-gal epitopes and produce the natural anti-Gal antibody which binds specifically to α-gal epitopes. Because of this reciprocal distribution of the α-gal epitope and anti-Gal in mammals, transplantation of organs from non-primate mammals (e.g., pig xenografts) into Old-World monkeys or humans results in hyperacute rejection following anti-Gal binding to α-gal epitopes on xenograft cells. The in vivo immunocomplexing between anti-Gal and α-gal epitopes on molecules, pathogens, cells, or nanoparticles may be harnessed for development of novel immunotherapies (referred to as “α-gal therapies”) in various clinical settings because such immune complexes induce several beneficial immune processes. These immune processes include localized activation of the complement system which can destroy pathogens and generate chemotactic peptides that recruit antigen-presenting cells (APCs) such as macrophages and dendritic cells, targeting of antigens presenting α-gal epitopes for extensive uptake by APCs, and activation of recruited macrophages into pro-reparative macrophages. Some of the suggested α-gal therapies associated with these immune processes are as follows: 1. Increasing efficacy of enveloped-virus vaccines by synthesizing α-gal epitopes on vaccinating inactivated viruses, thereby targeting them for extensive uptake by APCs. 2. Conversion of autologous tumors into antitumor vaccines by expression of α-gal epitopes on tumor cell membranes. 3. Accelerating healing of external and internal injuries by α-gal nanoparticles which decrease the healing time and diminish scar formation. 4. Increasing anti-Gal–mediated protection against zoonotic viruses presenting α-gal epitopes and against protozoa, such as Trypanosoma, Leishmania, and Plasmodium, by vaccination for elevating production of the anti-Gal antibody. The efficacy and safety of these therapies were demonstrated in transgenic mice and pigs lacking α-gal epitopes and producing anti-Gal, raising the possibility that these α-gal therapies may be considered for further evaluation in clinical trials.

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Antigen-Mediated, Macrophage-Stimulated, Accelerated Wound Healing Using α-Gal Nanoparticles

Abstract: Application of α-gal-containing nanoparticles to wounds stimulated a transiently increased inflammatory response, accelerating the rate of wound healing. Use of α-gal may be a simple and effective way to stimulate the wound healing response in both normal and pathologic wound beds.

Cited by 14 publications

References 34 publications

Near Complete Repair After Myocardial Infarction in Adult Mice by Altering the Inflammatory Response With Intramyocardial Injection of α-Gal Nanoparticles

Near Complete Repair After Myocardial Infarction in Adult Mice by Altering the Inflammatory Response With Intramyocardial Injection of α-Gal Nanoparticles

Topical α-Gal Nanoparticles Enhance Wound Healing in Radiated Skin

Biosynthesis of α-Gal Epitopes (Galα1-3Galβ1-4GlcNAc-R) and Their Unique Potential in Future α-Gal Therapies

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