Repeated Intravenous Administration of hiPSC-MSCs Enhance The Efficacy of Cell-Based Therapy In Tissue Regeneration

Abstract We sought to demonstrate whether therapeutic efficacy can be improved by combination of repeated intravenous administration and local transplantation of human induced pluripotential stem cell derived MSCs (hiPSC-MSCs). In this study, mice model of hind-limb ischemia was established by ligation of left femoral artery. hiPSC-MSCs (5x105) was intravenously administrated immediately after induction of hind limb ischemia with or without following intravenous administration of hiPSC-MSCs every week or every 3 days. Intramuscular transplantation of hiPSC-MSCs (3x106) was performed one week after induction of hind-limb ischemia. We compared the therapeutic efficacy and cell survival of intramuscular transplantation of hiPSC-MSCs with or without a single or repeated intravenous administration of hiPSC-MSCs. Repeated intravenous administration of hiPSC-MSCs could increase splenic regulatory T cells (Tregs) activation, decrease splenic natural killer (NK) cells expression, promote the polarization of M2 macrophages in the ischemic area and improved blood perfusion in the ischemic limbs. The improved therapeutic efficacy of MSC-based therapy was due to both increased engraftment of intramuscular transplanted hiPSC-MSCs and intravenous infused hiPSC-MSCs. In conclusion, our study supported a combination of repeated systemic infusion and local transplantation of hiPSC-MSCs for cardiovascular disease.

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CD151 Promotes Neovascularization and Improves Blood Perfusion in a Rat Hind-Limb Ischemia Model

Journal of Endovascular Therapy ◽

10.1583/04-1478r.1 ◽

2005 ◽

Vol 12 (4) ◽

pp. 469-478 ◽

Cited By ~ 21

Author(s):

Rong Fang Lan ◽

Zheng Xiang Liu ◽

Xiao Chun Liu ◽

Yu E. Song ◽

Dao Wen Wang

Keyword(s):

Hind Limb ◽

Blood Perfusion ◽

Limb Ischemia ◽

Hind Limb Ischemia

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Overexpression of glutaredoxin-1 stimulates revascularization and improves blood perfusion in a murine hind-limb ischemia model

Journal of the American College of Surgeons ◽

10.1016/j.jamcollsurg.2013.07.048 ◽

2013 ◽

Vol 217 (3) ◽

pp. S28

Author(s):

Salim Abunnaja ◽

Vaithinathan Selvara ◽

Mahesh Thirunavukka ◽

David Mcfadden ◽

J. Alexander Palesty ◽

...

Keyword(s):

Hind Limb ◽

Blood Perfusion ◽

Limb Ischemia ◽

Hind Limb Ischemia

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Deletion of Newly Described Molecule, Pellino1, Aggravates Blood Perfusion and Neovascularization and Exerts Increased Tissue Fibrosis in a Murine Model of Hind-Limb Ischemia

Journal of the American College of Surgeons ◽

10.1016/j.jamcollsurg.2015.07.423 ◽

2015 ◽

Vol 221 (4) ◽

pp. S178

Author(s):

Muhammad T. Rishi ◽

Inam A. Shaikh ◽

Vaithinathan Selvaraju ◽

David W. McFadden ◽

J. Alexander Palesty ◽

...

Keyword(s):

Murine Model ◽

Hind Limb ◽

Blood Perfusion ◽

Limb Ischemia ◽

Tissue Fibrosis ◽

Hind Limb Ischemia

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Abstract 16320: Enhanced Tissue Repair by Myoblast Administration With Extracellular Matrix Framework Through Regulation of Macrophage Polarization in Hind Limb Ischemia

Circulation ◽

10.1161/circ.142.suppl_3.16320 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Keisuke Miyake ◽

Shigeru Miyagawa ◽

Takashi Shibuya ◽

Yoshiki Sawa

Keyword(s):

Tissue Regeneration ◽

Muscle Regeneration ◽

Hind Limb ◽

Macrophage Polarization ◽

Limb Ischemia ◽

Skeletal Muscle Regeneration ◽

M2 Macrophages ◽

Hind Limb Ischemia ◽

Anti Inflammatory ◽

Myoblast Cells

Introduction: How to control inflammation, especially induction of macrophage polarization that are regulated by Extra-cellular matrix (ECM) is a prerequisite for tissue regeneration in damaged organs. In this study, we administered clustered myoblast cells with ECM framework into hind limb ischemia (HLI) model, and evaluated the change in macrophages and effect on tissue regeneration. Methods: Myoblast cells isolated from C57BL/6 mice were expanded to form cell patch with ECM framework (10 6 cells/sheet) and then fragmented and administered as cluster cells (CC group, n=6). As control groups, non-clustered single myoblast cells (SC, n=6) or saline (SA, n=6) was administered. Blood perfusion was evaluated with Laser Doppler Perfusion imaging (LDPI). Leg muscles were obtained and analyzed regarding angiogenesis, skeletal muscle regeneration, and inflammation including macrophage status. Results: LDPI showed significant improvement in CC compared with SC (P=0.001) and SA (P<0.0001) at day 28. Also, markedly augmented angiogenesis and muscle regeneration were detected in CC. Regarding inflammation, the number of CD68+ macrophages is significantly larger in CC throughout within 7 days after administration, but the character of the macrophages was quite different during time courses. Although in SC and SA macrophage polarization was rarely detected within 7 days, marked polarization was detected at day 5 only in CC. At day 5, CD11c+/CD206- (inflammatory, M1) and CD11c-/CD206+ (anti-inflammatory, M2) macrophages are discerned conspicuously (M1: 148.7±104.4/mm 2 , M2: 185.2±46.3/mm 2 , non-polarized CD11c+/CD206+: 140.9±99.4/mm 2 ), while at day 3 non-polarized macrophages were almost exclusive (M1: 2.0±2.3/mm 2 , M2: 3.1±4.0/mm 2 , CD11c+/CD206+: 410.2±90.6/mm 2 ). Consistently significant increase in IL-10 and TGF-β, that are cytokines secreted by M2 macrophages, was detected at day 5 and 7 in CC. Conclusions: Myoblast cells administration with ECM framework, which was formed during cell patch formation, augmented macrophage polarization to show anti-inflammatory effect, creating appropriate microenvironment for angiogenesis and muscle regeneration in HLI.

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Adverse Effect of Circadian Rhythm Disorder on Reparative Angiogenesis in Hind Limb Ischemia

Journal of the American Heart Association ◽

10.1161/jaha.121.020896 ◽

2021 ◽

Author(s):

Kazuhito Tsuzuki ◽

Yuuki Shimizu ◽

Junya Suzuki ◽

Zhongyue Pu ◽

Shukuro Yamaguchi ◽

...

Keyword(s):

Circadian Rhythm ◽

Hind Limb ◽

Umbilical Vein ◽

Blood Perfusion ◽

Limb Ischemia ◽

Jet Lag ◽

Double Knockout ◽

Hind Limb Ischemia ◽

Lag Model ◽

Reparative Angiogenesis

Background Circadian rhythm disorders, often seen in modern lifestyles, are a major social health concern. The aim of this study was to examine whether circadian rhythm disorders would influence angiogenesis and blood perfusion recovery in a mouse model of hind limb ischemia. Methods and Results A jet‐lag model was established in C57BL/6J mice using a light‐controlled isolation box. Control mice were kept at a light/dark 12:12 (12‐hour light and 12‐hour dark) condition. Concentrations of plasma vascular endothelial growth factor and circulating endothelial progenitor cells in control mice formed a circadian rhythm, which was diminished in the jet‐lag model ( P <0.05). The jet‐lag condition deteriorated tissue capillary formation ( P <0.001) and tissue blood perfusion recovery ( P <0.01) in hind limb ischemia, which was associated with downregulation of vascular endothelial growth factor expression in local ischemic tissue and in the plasma. Although the expression of clock genes (ie, Clock , Bmal1 , and Cry ) in local tissues was upregulated after ischemic injury, the expression levels of cryptochrome (Cry) 1 and Cry2 were inhibited by the jet‐lag condition. Next, Cry1 and Cry2 double‐knockout mice were examined for blood perfusion recoveries and a reparative angiogenesis. Cry1 and Cry2 double‐knockout mice revealed suppressed capillary density ( P <0.001) and suppressed tissue blood perfusion recovery ( P <0.05) in the hind limb ischemia model. Moreover, knockdown of CRY1/2 in human umbilical vein endothelial cells was accompanied by increased expression of WEE1 and decreased expression of HOXC5 . This was associated with decreased proliferative capacity, migration ability, and tube formation ability of human umbilical vein endothelial cells, respectively, leading to impairment of angiogenesis. Conclusions Our data suggest that circadian rhythm disorder deteriorates reparative ischemia‐induced angiogenesis and that maintenance of circadian rhythm plays an important role in angiogenesis.

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Glycation of Apolipoprotein A-IV Impairs Angiogenesis Through The Orphan Nuclear Receptor Nur77

10.21203/rs.3.rs-468317/v1 ◽

2021 ◽

Author(s):

Hongjuan Liu ◽

Yang Dai ◽

Yawei Xu ◽

Lin Lu

Keyword(s):

Hind Limb ◽

In Vitro Study ◽

Blood Perfusion ◽

Limb Ischemia ◽

Tube Formation ◽

Orphan Nuclear Receptor ◽

Hind Limb Ischemia ◽

Ischemic Tissue ◽

Collateral Growth

Abstract Background Apo A-Ⅳ played an key role in Cardiovascular diseases, but the effect and mechanism of glycated apo A-Ⅳ on angiogenesis remains unclear. Methods In this study, we demonstrated that oral administration of glycated apoA-Ⅳ impaired blood perfusion recovery in a mouse hind-limb ischemia model. A reduction in blood perfusion recovery at day 21 was observed in the ischemic tissue of apoA-Ⅳ and glycated apoA-Ⅳ-treated mice. Results In this study, we demonstrated that glycated apo A-Ⅳ impaired blood perfusion recovery in a mouse hind-limb ischemia model. And in vitro study also showed that glycated apo A-Ⅳ inhibited the migration, proliferation, and tube-formation abilities of endothelial cells. Further research revealed that glycated apo A-Ⅳ regulated angiogenesis partly by interrupting Nur77. In addition, CML levels were increased in patients with Lower limb circulation (n = 30) compared with those with no limb circulation(n = 50). Conclusions We found impaired angiogenesis induced by glycated apo A-Ⅳ might contribute to poor coronary collateral growth by inhibit the expression of Nur77.

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