Therapeutic angiogenesis for patients with no-option critical limb ischemia by adipose-derived regenerative cells: TACT-ADRC multicenter trial

Shimizu, Yasuhiko; Kondo, Kazuhisa; Hayashida, Ryo; Sasaki, Ken-ichiro; Ohtsuka, Masanori; Takashima, Shinya; Inoue, Oto; Usui, Soichiro; Takamura, Masayuki; Sakuma, Masashi; Inoue, Teruo; Nagata, Tokuichiro; Akashi, Yoshihiro; Yamada, Yoshihiro; Kato, Tamon; Kuwahara, Koichiro; Tateno, Kaoru; Kobayashi, Yoshio; Shibata, Rei; Murohara, Toyoaki

doi:10.1007/s10456-022-09844-7

Cited by 15 publications

(12 citation statements)

References 35 publications

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“…Our retrospective analysis of the SVF therapy trial for terminal CLI 46 supports a positive correlation between complete recovery and high numbers of injected CD271 + progenitors, while amputated/recurrence of CLI was associated with low numbers. Importantly, we determined that approximately 300,000 to 500,000 AT-CD271 + progenitors per lesion area (CD271 + cells / ulcer cm 2 ) as the dose that seems to be necessary for favorable outcome.…”

Section: Discussionsupporting

confidence: 64%

“…To further investigate the therapeutic potential of CD271 + progenitors, we retrospectively evaluated data from a limited human cell therapy trial (multi-center clinical trial of SVF therapy) for no-option CLI patients 47 ( Figure 7A and 7B ). During the one-year follow-up period, patients received no interventional treatments (e.g.…”

Section: Resultsmentioning

confidence: 99%

“…The detailed protocol and eligibility for the clinical trial of SVF therapy for CLI are published 46, 64 Briefly, this was a multicenter clinical trial to investigate the feasibility and safety of SVF injection for CLI patients with no option for treatment 46 . Autologous SVF from liposuction was transplanted to the ulcer lesions via intra-muscular injections.…”

Section: Methodsmentioning

confidence: 99%

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Single cell transcriptomics identifies adipose tissue CD271+ progenitors for enhanced angiogenesis in limb ischemia

Inoue¹,

Goten²,

Hashimuko³

et al. 2023

Preprint

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Therapeutic angiogenesis using mesenchymal stem/stromal cell grafts have shown modest and controversial effects in preventing amputation for patients with critical limb ischemia. Through single-cell transcriptomic analysis of human tissues, we identified CD271+progenitors specifically from subcutaneous adipose tissue (AT) as having the most prominent pro-angiogenic gene profile distinct from other stem cell populations. AT-CD271+progenitors demonstrated robust in vivo angiogenic capacity, over conventional adipose stromal cell grafts, characterized by long-term engraftment, augmented tissue regeneration, and significant recovery of blood flow in a xenograft model of limb ischemia. Mechanistically, the angiogenic capacity of CD271+progenitors is dependent on functional CD271 and mTOR signaling. Notably, the number and angiogenic capacity of CD271+progenitors was strikingly reduced in insulin resistant donors. Our study highlights the identification of AT- CD271+progenitors with in vivo superior efficacy for limb ischemia. Furthermore, we showcase comprehensive single-cell transcriptomics strategies for identification of suitable grafts for cell therapy.

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Section: Discussionsupporting

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Single cell transcriptomics identifies adipose tissue CD271+ progenitors for enhanced angiogenesis in limb ischemia

Inoue¹,

Goten²,

Hashimuko³

et al. 2023

Preprint

Self Cite

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“…This response triggers angiogenesis and collateral vessel development [ 133 , 134 ]. Therapeutic promotion of angiogenesis by delivery of VEGFA is therefore one approach in cases of acute ischemia [ 135 , 136 ]. Multiple strategies using growth factor- or cell-based therapies to promote blood vessel development have been described with different levels of success [ 137 , 138 ].…”

Section: Angiogenesis and Anti-angiogenesis In Diseasesmentioning

confidence: 99%

Pathological angiogenesis: mechanisms and therapeutic strategies

Dudley

2023

Angiogenesis

149

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In multicellular organisms, angiogenesis, the formation of new blood vessels from pre-existing ones, is an essential process for growth and development. Different mechanisms such as vasculogenesis, sprouting, intussusceptive, and coalescent angiogenesis, as well as vessel co-option, vasculogenic mimicry and lymphangiogenesis, underlie the formation of new vasculature. In many pathological conditions, such as cancer, atherosclerosis, arthritis, psoriasis, endometriosis, obesity and SARS-CoV-2(COVID-19), developmental angiogenic processes are recapitulated, but are often done so without the normal feedback mechanisms that regulate the ordinary spatial and temporal patterns of blood vessel formation. Thus, pathological angiogenesis presents new challenges yet new opportunities for the design of vascular-directed therapies. Here, we provide an overview of recent insights into blood vessel development and highlight novel therapeutic strategies that promote or inhibit the process of angiogenesis to stabilize, reverse, or even halt disease progression. In our review, we will also explore several additional aspects (the angiogenic switch, hypoxia, angiocrine signals, endothelial plasticity, vessel normalization, and endothelial cell anergy) that operate in parallel to canonical angiogenesis mechanisms and speculate how these processes may also be targeted with anti-angiogenic or vascular-directed therapies.

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“…Recently, the development of novel therapeutic angiogenesis cell sources, such as adipose-derived regenerative cells (ADRCs), has been investigated in no-option CLTI patients [ 22 ]. The results of this multicenter clinical trial demonstrated the safety, feasibility, and effectiveness of autologous ADRCs implantation for therapeutic angiogenesis, resulting in high major amputation-free survival rates (94.1%) at 6 months in no-option CLTI patients.…”

Section: Discussionmentioning

confidence: 99%

Duplex and Angiographic-Assisted Evaluation of Outcomes of Endovascular Embolization after Surgical Deep Vein Arterialization for the Treatment No-Option Critical Limb Ischemia Patients

Montelione¹,

Catanese²,

Gabellini

et al. 2022

Diagnostics

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Objective: To report early and mid-term outcomes of the arterialization of the deep venous system in no-option critical limb-threatening ischemia (CLTI) using duplex ultrasound and angiographic evaluation to improve limb perfusion. Methods: A single-center prospective study of patients with no-option CLTI treated with hybrid surgical arterialization of the deep venous circulation and staged endovascular embolization of the venous collateral. Embolization was performed using a controlled-release spiral, within two weeks after bypass surgery. Patients were assessed for clinical status, wound healing, median transcutaneous partial pressure of O2 (TcPO2), and post-operative duplex ultrasound evaluating peak systolic velocity (PSV), end diastolic velocity (EDV), and resistance index (RI) to assess foot perfusion and bypass features. Primary endpoint analysis was primary technical success, limb salvage, patency rates, and clinical improvement. Secondary endpoints were 30-day and long-term mortality, major cardiovascular events (MACE), including myocardial infarction or stroke, and serious adverse events (SAE). Results: Five patients with no-option CLTI were treated at our center using the hybrid deep vein arterialization technique. Clinical stage was grade 3 in one patient and grade 4 in the remaining four. Mean age was 65.8 years (range 49–76 years), and two patients were affected by Buerger’s disease. Primary technical success was achieved in all patients, and all the bypasses were patent at the angiographic examination. At 30-day and at average follow-up of 9.8 months (range 2–24 months), mortality, major cardiovascular events (MACE), and serious adverse events (SAE) were not reported, with a primary patency and limb salvage rates of 100%. Three patients required minor amputation. Clinical improvement was demonstrated in all patients with granulation, resolution of rest pain, or both. Median TcPO2 values rose from 10 mm Hg (range 4–25) before the procedure to 35 (range 31–57) after surgery, and to 59 mm Hg (range 50–76) after the staged endovascular procedure. Conclusions: In our initial experience, the arterialization of the deep venous circulation, with subsequent selective embolization of the venous escape routes from the foot, seems a feasible and effective solution for limb salvage in patients with no-option CLTI and those in the advanced wound, ischemia, and foot infection (WIfI) clinical stage.

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Therapeutic angiogenesis for patients with no-option critical limb ischemia by adipose-derived regenerative cells: TACT-ADRC multicenter trial

Cited by 15 publications

References 35 publications

Single cell transcriptomics identifies adipose tissue CD271+ progenitors for enhanced angiogenesis in limb ischemia

Single cell transcriptomics identifies adipose tissue CD271+ progenitors for enhanced angiogenesis in limb ischemia

Pathological angiogenesis: mechanisms and therapeutic strategies

Duplex and Angiographic-Assisted Evaluation of Outcomes of Endovascular Embolization after Surgical Deep Vein Arterialization for the Treatment No-Option Critical Limb Ischemia Patients

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