Safety and Effect of Adipose Tissue-Derived Stem Cell Implantation in Patients With Critical Limb Ischemia

Lee, Han Cheol; An, Sung Gyu; Lee, Hye Won; Park, Jin-Sup; Soo, Kwang; Hong, Taek Jong; Park, Jong Ha; Lee, Sun Young; Kim, Sang-Pil; Kim, Yeong‐Dae; Chung, Sung Woon; Bae, Yong Chan; Shin, Yong Beom; Kim, Jeung Il; Jung, Jin Sup

doi:10.1253/circj.cj-11-1135

Cited by 250 publications

(135 citation statements)

References 39 publications

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“…Adipose-derived stem cells have been successfully and safely implanted in patients with CLI and evidence from a Korean trial (n ¼ 15) published in 2012 showed that there was a significant clinical improvement in two-thirds of patients as measured by pain scores, amputation rates, claudication distance and appearance on angiography. 71 …”

Section: Alternate Stem Cellsmentioning

confidence: 99%

Stem cells of the lower limb: Their role and potential in management of critical limb ischemia

Hart

Tsui

Khanna

et al. 2013

Exp Biol Med (Maywood)

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Peripheral arterial occlusive disease (PAOD) contributes to decreased exercise tolerance, poor balance, impaired proprioception, muscle atrophy and weakness, with advanced cases resulting in critical limb ischemia (CLI) where the viability of the limb is threatened. Patients with a diagnosis of CLI have a poor life expectancy due to concomitant cardio and cerebrovascular diseases. The current treatment options to avoid major amputation by re-establishing a blood supply to the limb generally have poor outcomes. Human skeletal muscle contains both multipotent stem cells and progenitor cells and thus has a capacity for regeneration. Phase I and II studies involving transplantation of bone marrow-derived progenitor cells into CLI limbs show positive effects on wound healing and angiogenesis; the increase in quiescent satellite cell numbers observed in CLI muscle may also provide a sufficient in vivo source of resident stem cells. These indigenous cells have been shown to be capable of forming multiple mesodermal cell lineages aiding the repair and regeneration of chronically ischemic muscle. They may also serve as a repository for autologous transplantation. The behavior and responses of the stem cell population in CLI is poorly understood and this review tries to elucidate the potential of these cells and their future role in the management of CLI.

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Section: Alternate Stem Cellsmentioning

confidence: 99%

Stem cells of the lower limb: Their role and potential in management of critical limb ischemia

Hart

Tsui

Khanna

et al. 2013

Exp Biol Med (Maywood)

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“…Clinical trials using MSCs for treatment of ischemic diseases gave promising results but also demonstrated the need for further improvement [1,2,3]. The beneficial MSC effects range from improved vascularization and perfusion to the protection of ischemically damaged cells and favorable influences on tissue remodeling [4,5], notably in cardiac and skeletal muscle [6,7,8].…”

Section: Introductionmentioning

confidence: 99%

Cord Blood Mesenchymal Stromal Cell-Conditioned Medium Protects Endothelial Cells via STAT3 Signaling

Bader

Brodarac

Klose

et al. 2014

Cell Physiol Biochem

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Background/Aims: Cell-based therapies may be useful for treating ischemic diseases, but the underlying mechanisms are incompletely understood. We investigated the impact of cord blood mesenchymal stromal cell (CBMSC)- or fibroblast (FB)-secreted factors on starved endothelial cells and determined the relevant intracellular signaling pathways. Methods: HUVECs were subjected to glucose/serum deprivation (GSD) in hypoxia or normoxia, in presence of CBMSC- or FB-conditioned medium (CM). Viability and proliferation were determined via WST-8 conversion and BrdU incorporation. Apoptosis was quantified by annexin V/ethidium homodimer-III staining, nuclear fragmentation and cell morphology. mRNA expression and protein phosphorylation were determined by real-time qPCR and western blot. Experiments were repeated in presence of small-molecule inhibitors. Results: The negative impact of GSD was most pronounced at 21% O₂. Here, medium of CBMSCs and FBs increased viability and proliferation and reduced apoptosis of HUVECs. This was associated with increased STAT3 and ERK1/2 phosphorylation and BCL-2 expression. Under STAT3 inhibition, the beneficial effect of CBMSC-CM on viability and BCL-2 expression was abolished. Conclusion: Factors released by CBMSCs protect endothelial cells from the deleterious impact of GSD by activation of the STAT3 survival pathway. However, this phenomenon is not CBMSC-specific and can be reproduced using juvenile fibroblasts.

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“…In relation to this, several types of stem cells have been used to induce neovascularization in vitro and in animal models, leading to several clinical trials carried out to prove their safety and efficacy [2, 28]. Unfortunately, preliminary data have shown that a certain percentage of patients do not benefit from therapeutic angiogenesis [29, 30].…”

Section: Discussionmentioning

confidence: 99%

Analysis of Biological Properties of Human Adult Mesenchymal Stem Cells and Their Effect on Mouse Hind Limb Ischemia

et al. 2019

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Background: Due to their self-renewal, proliferation, differentiation, and angiogenesis-inducing capacity, human adipose mesenchymal stem cells (AMSC) have potential clinical applications in the treatment of limb ischemia. AMSC from healthy donors have been shown to induce neovascularization in animal models. However, when cells were obtained from donors suffering from any pathology, their autologous application showed limited effectiveness. We studied whether liposuction niche and obesity could determine the regenerative properties of cells meaning that not all cell batches are suitable for clinical practice. Methods: AMSC obtained from 10 donors, obese and healthy, were expanded in vitro following a good manufacturing practice-like production protocol. Cell viability, proliferation kinetics, morphological analysis, phenotype characterization, and stemness potency were assessed over the course of the expansion process. AMSC selected for having the most suitable biological properties were used as an experimental treatment in a preclinical mouse model of hind limb ischemia. Result: All cell batches were positively characterized as mesenchymal stem cells, but not all of them showed the same properties or were successfully expanded in vitro, depending on the characteristics of the donor and the extraction area. Notably, AMSC from the abdomen of obese donors showed undesirable biological properties. AMSC with low duplication times and multilineage differentiation potential and forming large densely packed colonies, were able, following expansion in vitro, to increase neovascularization and repair when implanted in the ischemic tissue of mice. Conclusion: An extensive AMSC biological properties study could be useful to predict the potential clinical efficacy of cells before in vivo transplantation. Thus, peripheral ischemia and possibly other pathologies could benefit from stem cell treatments as shown in our preclinical model in terms of tissue damage repair and regeneration after ischemic injury.

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Safety and Effect of Adipose Tissue-Derived Stem Cell Implantation in Patients With Critical Limb Ischemia

Cited by 250 publications

References 39 publications

Stem cells of the lower limb: Their role and potential in management of critical limb ischemia

Stem cells of the lower limb: Their role and potential in management of critical limb ischemia

Cord Blood Mesenchymal Stromal Cell-Conditioned Medium Protects Endothelial Cells via STAT3 Signaling

Analysis of Biological Properties of Human Adult Mesenchymal Stem Cells and Their Effect on Mouse Hind Limb Ischemia

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