Impact of Therapeutic Angiogenesis Using Autologous Bone Marrow-derived Mononuclear Cell Implantation in Patients with No-option Critical Limb Ischemia

Yanishi, Kenji; Kudoh, Shoji; Fujioka, Ayumu; Hori, Yusuke; Yukawa, Arito; Matoba, Satoaki

doi:10.3400/avd.ra.20-00002

Cited by 5 publications

(10 citation statements)

References 34 publications

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“…For these patients with no-option CLTI, therapeutic angiogenesis using BM-MNC implantation is a potential recourse. Multiple studies have shown the effectiveness and safety of BM-MNC implantation [13][14][15][16][17][18][19][20][21][22][23]. In 2008, Matoba et al reported that the OS and AFS rates at 3 years after BM-MNC implantation were 80% and 60%, respectively, in 74 patients with no-option CLTI resulting from atherosclerotic LEAD (TACT follow-up study) [17].…”

Section: Discussionmentioning

confidence: 99%

“…In a long-term prognosis analysis performed by Kondo et al, 374 patients with no-option CLTI due to atherosclerotic LEAD had OS rates at 1, 5, and 10 years after BM-MNC implantation of 95.6%, 87.3%, and 68.6%, respectively, and AFS rates of 82.7%, 71.8%, and 59.1%, respectively [20]. In addition, BM-MNC implantation has been reported to improve various indicators of limb ischemia, including the resting pain, pain-free walking distance, ulcer size, and transcutaneous partial pressure of oxygen (tcPO 2 ) [13–17, 22, 23].…”

Section: Discussionmentioning

confidence: 99%

“…This treatment primarily targets CLTI resulting from atherosclerotic LEAD, thromboangiitis obliterans (TAO), and collagen disease-associated vasculitis (CDV). Numerous clinical studies have reported the effectiveness and safety of BM-MNC implantation for CLTI [13][14][15][16][17][18][19][20][21][22][23]. However, limb salvage and survival rates after BM-MNC implantation in CLTI caused by atherosclerotic LEAD are worse than those in CLTI caused by the other two diseases (non-atherosclerotic LEAD) [13,17,18,20].…”

Section: Introductionmentioning

confidence: 99%

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Prognostic Predictors After Bone Marrow-Derived Mononuclear Cell Implantation in No-Option Chronic Limb-Threatening Ischemia Patients with Atherosclerotic Lower Extremity Artery Disease

Kawamata,

Yanishi,

Yoshimura

et al. 2023

Preprint

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Background: Previous studies have reported the efficacy and safety of therapeutic angiogenesis through bone marrow-derived mononuclear cell (BM-MNC) implantation in patients with no-option critical limb-threatening ischemia (CLTI) from atherosclerotic lower extremity artery disease (LEAD). However, uncertain clinical prognostic factors impact treatment outcomes. Methods: In this retrospective, single-center, observational study, we assessed the long-term prognosis post-treatment. Primary endpoints included the long-term prognosis of BM-MNC implantation and factors influencing 1-year outcomes. Results: A total of 92 limbs in 84 patients were analyzed in the final cohort. The mean age was 67 years, and 65% were male. The 5- and 10-year overall survival rates were 50.0% and 31.0%, respectively, while the 5- and 10-year amputation-free survival rates were 37.6% and 23.3%, respectively. Multivariate logistic analysis linked all-cause mortality to an age ?70 years, hemodialysis, smoking, and a controlling nutrition status score ?5. Major amputation or mortality was associated with male gender, hemodialysis, and C-reactive protein levels ?3.0 mg/dL. No adverse events were associated with therapeutic angiogenesis. Conclusions: These findings endorse the feasibility and safety of BM-MNC implantation for patients with no-option CLTI due to atherosclerotic LEAD. Moreover, the study highlights the significance of several prognostic factors, including advanced age, hemodialysis, smoking, and inflammatory markers, in influencing the long-term outcomes of this treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prognostic Predictors After Bone Marrow-Derived Mononuclear Cell Implantation in No-Option Chronic Limb-Threatening Ischemia Patients with Atherosclerotic Lower Extremity Artery Disease

Kawamata,

Yanishi,

Yoshimura

et al. 2023

Preprint

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“…BMMNCs are heterogeneous cell populations including stem cells (SCs), endothelial progenitor cells, monocytes and lymphocytes (39,40). A synergistic effect among the heterogeneous cell populations promotes neovascularisation even in previously avascular tissue (39,41,42).…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of Platelet-Rich Plasma and Bone Marrow Aspirate Concentrate as Treatments for Chronic Hindlimb Proximal Suspensory Desmopathy

Maleas

Mageed

2021

Front. Vet. Sci.

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This retrospective study aimed to evaluate the clinical effect of bone marrow aspirate concentrate (BMAC) and leukocyte rich PRP (LR-PRP) compared to horses undergoing controlled exercise alone in horses with >3 months proximal suspensory desmopathy in hindlimbs (HPSD). Nighty-three horses were divided into three groups according to the treatment: a control (n = 22), LR-PRP (n = 46), and BMAC (n = 25) group. Lameness and ultrasound scores were recorded before treatment (T0) and at 6 months (T1) post-treatment. Records horses considered sound at evaluation and level of performance were additionally registered at 12 months (T2) and 18 months (T3) after treatment. The BMAC cytology profiles from 22 horses were also analysed and compared to clinical outcomes. The results at T1 showed that 9% (2/22) of the horses in the control group were sound compared to 59% (25/46) and 84% (21/25) in the LR-PRP and BMAC groups, respectively. Additionally, ultrasound scores at T1 in the BMAC and LR-PRP groups were improved in comparison with the control group (p = 0.02). At T2, 68% of the horses in the BMAC group and 39% of the horses in the LR-PRP group had returned to the previous performance level. At T3, a significantly higher percentage of horses in the LR-PRP (43%) and BMAC (72%) group were sound when compared to the control (4.6%) group (p = 0.02). Similarly, at T3, significantly more horses of the BMAC (16/25) and of the LR-PRP (15/46) group had returned to the previous or a higher performance level compared to the control (1/22) group (p = 0.01). No correlation was found between long-term clinical outcome and cytology profiles in the BMAC group. In conclusion, long-term outcomes of treatment with LR-PRP or BMAC are significantly better than conventional treatment of the hindlimb chronic PSD in horses. Additionally, BMAC yielded better lameness scores than LR-PRP at short- and long-term follow-up.

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“…In this regard, some of the cells included in REX-001 product (enriched for MNC, as well as granulocytes and hematopoietic stem cells expressing CD34) might participate in the paracrine effect. For instance, circulating BM-derived EPC (CD34+CD45+) have been described as powerful angiogenic agents (Yanishi et al, 2020 ). These cells release angiogenic and chemo-attractant factors once migrated into the ischemic tissues, recruiting immune cells (neutrophils, monocytes) and activating other cells that will participate in the inflammatory response and also contribute to vascular remodeling (Beltran-Camacho et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

REX-001, a BM-MNC Enriched Solution, Induces Revascularization of Ischemic Tissues in a Murine Model of Chronic Limb-Threatening Ischemia

Rojas-Torres

Jiménez-Palomares

Martín-Ramírez³

et al. 2020

Front. Cell Dev. Biol.

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Background: Bone Marrow Mononuclear Cells (BM-MNC) constitute a promising alternative for the treatment of Chronic Limb-Threatening ischemia (CLTI), a disease characterized by extensive blockade of peripheral arteries, clinically presenting as excruciating pain at rest and ischemic ulcers which may lead to gangrene and amputation. BM-MNC implantation has shown to be efficient in promoting angiogenesis and ameliorating ischemic symptoms in CLTI patients. However, the variability seen between clinical trials makes necessary a further understanding of the mechanisms of action of BM-MNC, and moreover, to improve trial characteristics such as endpoints, inclusion/exclusion criteria or drug product compositions, in order to implement their use as stem-cell therapy.Materials: Herein, the effect of REX-001, a human-BM derived cell suspension enriched for mononuclear cells, granulocytes and CD34+ cells, has been assessed in a murine model of CLTI. In addition, a REX-001 placebo solution containing BM-derived red blood cells (BM-RBCs) was also tested. Thus, 24 h after double ligation of the femoral artery, REX-001 and placebo were administrated intramuscularly to Balb-c nude mice (n:51) and follow-up of ischemic symptoms (blood flow perfusion, motility, ulceration and necrosis) was carried out for 21 days. The number of vessels and vascular diameter sizes were measured within the ischemic tissues to evaluate neovascularization and arteriogenesis. Finally, several cell-tracking assays were performed to evaluate potential biodistribution of these cells.Results: REX-001 induced a significant recovery of blood flow by increasing vascular density within the ischemic limbs, with no cell translocation to other organs. Moreover, cell tracking assays confirmed a decrease in the number of infused cells after 2 weeks post-injection despite on-going revascularization, suggesting a paracrine mechanism of action.Conclusion: Overall, our data supported the role of REX-001 product to improve revascularization and ischemic reperfusion in CLTI.

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Impact of Therapeutic Angiogenesis Using Autologous Bone Marrow-derived Mononuclear Cell Implantation in Patients with No-option Critical Limb Ischemia

Cited by 5 publications

References 34 publications

Prognostic Predictors After Bone Marrow-Derived Mononuclear Cell Implantation in No-Option Chronic Limb-Threatening Ischemia Patients with Atherosclerotic Lower Extremity Artery Disease

Prognostic Predictors After Bone Marrow-Derived Mononuclear Cell Implantation in No-Option Chronic Limb-Threatening Ischemia Patients with Atherosclerotic Lower Extremity Artery Disease

Effectiveness of Platelet-Rich Plasma and Bone Marrow Aspirate Concentrate as Treatments for Chronic Hindlimb Proximal Suspensory Desmopathy

REX-001, a BM-MNC Enriched Solution, Induces Revascularization of Ischemic Tissues in a Murine Model of Chronic Limb-Threatening Ischemia

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