-
Stem Cell Research & Therapy Aug 2023Peripheral artery disease is an ischemic vascular disease caused by the blockage of blood vessels supplying blood to the lower extremities. Mesenchymal stem cells (MSCs)...
BACKGROUND
Peripheral artery disease is an ischemic vascular disease caused by the blockage of blood vessels supplying blood to the lower extremities. Mesenchymal stem cells (MSCs) and endothelial colony-forming cells (ECFCs) have been reported to alleviate peripheral artery disease by forming new blood vessels. However, the clinical application of MSCs and ECFCs has been impeded by their poor in vivo engraftment after cell transplantation. To augment in vivo engraftment of transplanted MSCs and ECFCs, we investigated the effects of hybrid cell spheroids, which mimic a tissue-like environment, on the therapeutic efficacy and survival of transplanted cells.
METHODS
The in vivo survival and angiogenic activities of the spheroids or cell suspension composed of MSCs and ECFCs were measured in a murine hindlimb ischemia model and Matrigel plug assay. In the hindlimb ischemia model, the hybrid spheroids showed enhanced therapeutic effects compared with the control groups, such as adherent cultured cells or spheroids containing either MSCs or ECFCs.
RESULTS
Spheroids from MSCs, but not from ECFCs, exhibited prolonged in vivo survival compared with adherent cultured cells, whereas hybrid spheroids composed of MSCs and ECFCs substantially increased the survival of ECFCs. Moreover, single spheroids of either MSCs or ECFCs secreted greater levels of pro-angiogenic factors than adherent cultured cells, and the hybrid spheroids of MSCs and ECFCs promoted the secretion of several pro-angiogenic factors, such as angiopoietin-2 and platelet-derived growth factor.
CONCLUSION
These results suggest that hybrid spheroids containing MSCs can serve as carriers for cell transplantation of ECFCs which have poor in vivo engraftment efficiency.
Topics: Humans; Animals; Mice; Neovascularization, Physiologic; Endothelial Cells; Mesenchymal Stem Cells; Cells, Cultured; Ischemia; Peripheral Arterial Disease
PubMed: 37533021
DOI: 10.1186/s13287-023-03435-z -
The American Journal of Case Reports Apr 2022BACKGROUND Cogan syndrome is a rare autoimmune disorder associated most frequently with ocular, vestibular, and auditory involvement from presumed small vessel...
BACKGROUND Cogan syndrome is a rare autoimmune disorder associated most frequently with ocular, vestibular, and auditory involvement from presumed small vessel vasculitis. Cogan syndrome, in a significant proportion of patients, can progress to systemic symptoms, including gastrointestinal, neurologic, and musculoskeletal manifestations. Large-vessel involvement has also been described in some cases (eg, aortitis), but acute limb ischemia in the setting of this illness has been infrequently reported. CASE REPORT We present a rare case of Cogan syndrome complicated by acute vascular ischemia of the left upper extremity. A 50-year-old man presented with symptoms of severe acute pain and weakness of the left arm. The patient endorsed a diagnosis of Cogan syndrome 4 years prior in the setting of unilateral left-sided hearing loss and bilateral uveitis. A physical examination revealed pallor of the left forearm and pulselessness at the wrist. Computed tomography angiography was suggestive of vasculitis and concerns for embolic occlusion of several arterial structures of the left upper limb. After consultation with various specialists, the patient was treated with high-dose steroids, anticoagulants, and topical nitroglycerin and experienced significant clinical improvement. CONCLUSIONS Treatment of Cogan syndrome with severe systemic manifestations depends on the organ involvement and degree of extension. Our patient's presentation serves as an impressive example of systemic vasculitis with subsequent acute ischemia in the setting of this rare autoimmune disorder. In such a case, given the potential for life- or limb-threatening systemic vascular catastrophes, emergent interventions (including imaging, anticoagulation, and specialist involvement) are required to prevent untoward outcomes.
Topics: Apraxias; Autoimmune Diseases; Cogan Syndrome; Humans; Ischemia; Male; Middle Aged; Peripheral Vascular Diseases; Vasculitis
PubMed: 35488414
DOI: 10.12659/AJCR.935929 -
Advanced Science (Weinheim,... Apr 2021Chronic limb threatening ischemia (CLTI) is a severe condition defined by the blockage of arteries in the lower extremities that leads to the degeneration of blood... (Review)
Review
Chronic limb threatening ischemia (CLTI) is a severe condition defined by the blockage of arteries in the lower extremities that leads to the degeneration of blood vessels and is characterized by the formation of non-healing ulcers and necrosis. The gold standard therapies such as bypass and endovascular surgery aim at the removal of the blockage. These therapies are not suitable for the so-called "no option patients" which present multiple artery occlusions with a likelihood of significant limb amputation. Therefore, CLTI represents a significant clinical challenge, and the efforts of developing new treatments have been focused on stimulating angiogenesis in the ischemic muscle. The delivery of pro-angiogenic nucleic acid, protein, and stem cell-based interventions have limited efficacy due to their short survival. Engineered biomaterials have emerged as a promising method to improve the effectiveness of these latter strategies. Several synthetic and natural biomaterials are tested in different formulations aiming to incorporate nucleic acid, proteins, stem cells, macrophages, or endothelial cells in supportive matrices. In this review, an overview of the biomaterials used alone and in combination with growth factors, nucleic acid, and cells in preclinical models is provided and their potential to induce revascularization and regeneration for CLTI applications is discussed.
Topics: Biocompatible Materials; Chronic Disease; Humans; Ischemia; Limb Salvage; Lower Extremity; Peripheral Arterial Disease
PubMed: 33854887
DOI: 10.1002/advs.202003119 -
Medicine May 2023The diagnosis of mesenteric ischemia in critically ill patients remains challenging; however, the aquarium sign, comprising a large number of bubble images in the right...
RATIONALE
The diagnosis of mesenteric ischemia in critically ill patients remains challenging; however, the aquarium sign, comprising a large number of bubble images in the right cardiac chambers on echocardiography, may be used as a point-of-care ultrasound finding to diagnose acute mesenteric ischemia (AMI).
PATIENT CONCERNS
A 65-year-old woman diagnosed with lymphoma was urgently admitted to the intensive care unit with suspected tumor lysis syndrome. High-dose vasopressor and inotropic agents were required to manage the patient's shock with marked lactic acidosis and peripheral hypoperfusion with mottled skin, and multidisciplinary treatment was initiated. By day 6, the lactate levels normalized and there were no abnormal abdominal findings. An echocardiogram was performed to examine the mass lesion associated with lymphoma in the right atrium and evaluate the hemodynamics; it revealed an "aquarium sign." Similar findings were found in the inferior vena cava and portal vein.
DIAGNOSES
Contrast-enhanced computed tomography of the abdomen revealed hepatic portal vein gas, poor contrast of the colon wall, and intramural emphysema, and a diagnosis of AMI was made. Lower gastrointestinal endoscopy showed necrosis of the colon.
INTERVENTIONS
The patient underwent urgent subtotal colorectal resection.
OUTCOMES
Although a tracheostomy was required, the patient's general condition improved after surgery, and she was discharged to the ward without mechanical ventilatory support in the intensive care unit on Day 19.
LESSONS
In patients with risk factors for AMI, repeated evaluation for the presence of aquarium signs by echocardiography may be warranted, even if there are no abdominal findings or abnormalities in biomarkers, such as lactate levels and trends. When the aquarium sign is found, AMI should be aggressively suspected, and a definitive diagnosis should be made to initiate early therapeutic intervention.
Topics: Female; Humans; Aged; Mesenteric Ischemia; Vena Cava, Inferior; Portal Vein; Tomography, X-Ray Computed; Lactates; Ischemia
PubMed: 37171317
DOI: 10.1097/MD.0000000000033735 -
Cell Reports. Medicine Dec 2023Therapeutic angiogenesis using mesenchymal stem/stromal cell grafts have shown modest and controversial effects in preventing amputation for patients with critical limb...
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 identify 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 demonstrate 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 are 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.
Topics: Humans; Adapalene; Angiogenesis; Gene Expression Profiling; Adipose Tissue; Ischemia
PubMed: 38118404
DOI: 10.1016/j.xcrm.2023.101337 -
Modulation of Mesenchymal Stem Cells for Enhanced Therapeutic Utility in Ischemic Vascular Diseases.International Journal of Molecular... Dec 2021Mesenchymal stem cells are multipotent stem cells isolated from various tissue sources, including but not limited to bone marrow, adipose, umbilical cord, and Wharton... (Review)
Review
Mesenchymal stem cells are multipotent stem cells isolated from various tissue sources, including but not limited to bone marrow, adipose, umbilical cord, and Wharton Jelly. Although cell-mediated mechanisms have been reported, the therapeutic effect of MSCs is now recognized to be primarily mediated via paracrine effects through the secretion of bioactive molecules, known as the "secretome". The regenerative benefit of the secretome has been attributed to trophic factors and cytokines that play neuroprotective, anti-angiogenic/pro-angiogenic, anti-inflammatory, and immune-modulatory roles. The advancement of autologous MSCs therapy can be hindered when introduced back into a hostile/disease environment. Barriers include impaired endogenous MSCs function, limited post-transplantation cell viability, and altered immune-modulatory efficiency. Although secretome-based therapeutics have gained popularity, many translational hurdles, including the heterogeneity of MSCs, limited proliferation potential, and the complex nature of the secretome, have impeded the progress. This review will discuss the experimental and clinical impact of restoring the functional capabilities of MSCs prior to transplantation and the progress in secretome therapies involving extracellular vesicles. Modulation and utilization of MSCs-secretome are most likely to serve as an effective strategy for promoting their ultimate success as therapeutic modulators.
Topics: Animals; Clinical Trials as Topic; Humans; Ischemia; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Vascular Diseases; Wound Healing
PubMed: 35008675
DOI: 10.3390/ijms23010249 -
Annals of Vascular Surgery Aug 2022COVID-19 was initially identified as an acute respiratory disease, but it was quickly recognized that multiple organ systems could be affected. Venous thrombosis and...
BACKGROUND
COVID-19 was initially identified as an acute respiratory disease, but it was quickly recognized that multiple organ systems could be affected. Venous thrombosis and pulmonary embolism have been well reported. However, there is a paucity of data on COVID-19-related arterial thrombosis. We examined the incidence, characteristics, treatment, and outcome in patients with acute COVID-19-related arterial thrombosis in a large health maintenance organization (HMO).
METHODS
A retrospective multicenter case review was performed from March 2020 to March 2021. Cases were identified through a questionnaire sent to vascular surgeons. Patient characteristics, imaging, treatment, and outcome were reviewed. Successful revascularization was defined as restoration of blood flow with viability of the end organ and absence of death within 30 days. Limb salvage was defined as prevention of major amputation (transtibial or transfemoral) and absence of death in 30 days.
RESULTS
There were 37,845 patients admitted with COVID-19 complications during this time. Among this group, 26 patients (0.07%) had COVID-19-related arterial thrombosis. The mean age was 61.7 years (range, 33-82 years) with 20 men (77%) and 6 women (23%). Ethnic minorities comprised 25 of 26 cases (96%). Peripheral arterial disease (PAD) was present in 4 of 26 (15%), active smoking in 1 of 26 (3.8%), and diabetes in 19 of 26 (73%) cases. Most patients developed acute arterial ischemia in the outpatient setting, 20 of 26 (77%). Of the outpatients, 6 of 20 (30%) had asymptomatic COVID-19 and 14 of 20 (70%) had only mild upper respiratory symptoms. Distribution of ischemia was as follows: 23 patients had at least one lower extremity ischemia, one patient had cerebral and lower extremity, one had mesenteric and lower extremity, and one had upper extremity ischemia. Revascularization was attempted in 21 patients, of which 12 of 21 (57%) were successful. Limb salvage was successful in 13 of 26 (50%) patients. The overall mortality was 31% (8/26).
CONCLUSIONS
Our experience in a large HMO revealed that the incidence of COVID-19-related arterial thrombosis was low. The actual incidence is likely to be higher since our method of case collection was incomplete. The majority of arterial thrombosis occurred in the outpatient setting in patients with asymptomatic or mild/moderate COVID-19 respiratory disease. Acute ischemia was the inciting factor for hospitalization in these cases. Acute lower extremity ischemia was the most common presentation, and limb salvage rate was lower than that expected when compared to ischemia related to PAD. Arterial thrombosis associated with COVID-19 portends a significantly higher mortality. Education of primary care providers is paramount to prevent delayed diagnosis as most patients initially developed ischemia in the outpatient setting and did not have a high cardiovascular risk profile.
Topics: Amputation, Surgical; Arterial Occlusive Diseases; COVID-19; Female; Health Maintenance Organizations; Humans; Ischemia; Limb Salvage; Lower Extremity; Male; Middle Aged; Peripheral Arterial Disease; Retrospective Studies; Risk Factors; Thrombosis; Treatment Outcome
PubMed: 35470048
DOI: 10.1016/j.avsg.2022.04.024 -
Arteriosclerosis, Thrombosis, and... May 2024Elevated apoB-containing lipoproteins (=remnants+LDLs [low-density lipoproteins]) are a major risk factor for atherosclerotic cardiovascular disease, including... (Comparative Study)
Comparative Study
BACKGROUND
Elevated apoB-containing lipoproteins (=remnants+LDLs [low-density lipoproteins]) are a major risk factor for atherosclerotic cardiovascular disease, including peripheral artery disease (PAD) and myocardial infarction. We tested the hypothesis that remnants and LDL both explain part of the increased risk of PAD conferred by elevated apoB-containing lipoproteins. For comparison, we also studied the risk of chronic limb-threatening ischemia and myocardial infarction.
METHODS
apoB, remnant cholesterol, and LDL cholesterol were measured in 93 461 individuals without statin use at baseline from the Copenhagen General Population Study (2003-2015). During up to 15 years of follow-up, 1207 had PAD, 552 had chronic limb-threatening ischemia, and 2022 had myocardial infarction in the Danish National Patient Registry. Remnant and LDL cholesterol were calculated from a standard lipid profile. Remnant and LDL particle counts were additionally measured with nuclear magnetic resonance spectroscopy in 25 347 of the individuals. Results were replicated in 302 167 individuals without statin use from the UK Biobank (2004-2010).
RESULTS
In the Copenhagen General Population Study, multivariable adjusted hazard ratios for risk of PAD per 1 mmol/L (39 mg/dL) increment in remnant and LDL cholesterol were 1.9 (95% CI, 1.5-2.4) and 1.1 (95% CI, 1.0-1.2), respectively; corresponding results in the UK Biobank were 1.7 (95% CI, 1.4-2.1) and 0.9 (95% CI, 0.9-1.0), respectively. In the association from elevated apoB to increased risk of PAD, remnant and LDL cholesterol explained 73% (32%-100%) and 8% (0%-46%), respectively; corresponding results were 63% (30%-100%) and 0% (0%-33%) for risk of chronic limb-threatening ischemia and 41% (27%-55%) and 54% (38%-70%) for risk of myocardial infarction; results for remnant and LDL particle counts corroborated these findings.
CONCLUSIONS
PAD risk conferred by elevated apoB-containing lipoproteins was explained mainly by elevated remnants, while myocardial infarction risk was explained by both elevated remnants and LDL.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Apolipoprotein B-100; Biomarkers; Cholesterol; Cholesterol, LDL; Denmark; Ischemia; Lipoproteins; Myocardial Infarction; Peripheral Arterial Disease; Prospective Studies; Registries; Risk Assessment; Risk Factors; Time Factors; Triglycerides
PubMed: 38511326
DOI: 10.1161/ATVBAHA.123.320175 -
Journal of Vascular Surgery Apr 2023Patients with peripheral artery disease (PAD) requiring lower extremity revascularization (LER) have a high risk of adverse limb and cardiovascular events. The results... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with peripheral artery disease (PAD) requiring lower extremity revascularization (LER) have a high risk of adverse limb and cardiovascular events. The results from the VOYAGER PAD (efficacy and safety of rivaroxaban in reducing the risk of major thrombotic vascular events in subjects with symptomatic peripheral artery disease undergoing peripheral revascularization procedures of the lower extremities) trial have demonstrated that rivaroxaban significantly reduced this risk with an overall favorable net benefit for patients undergoing surgical revascularization. However, the efficacy and safety for those treated by surgical bypass, including stratification by bypass conduit (venous or prosthetic), has not yet been described.
METHODS
In the VOYAGER PAD trial, patients who had undergone surgical and endovascular infrainguinal LER to treat PAD were randomized to rivaroxaban 2.5 mg twice daily or placebo on top of background antiplatelet therapy (aspirin 100 mg to be used in all and clopidogrel in some at the treating physician's discretion) and followed up for a median of 28 months. The primary end point was a composite of acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke, and cardiovascular death. The principal safety outcome was major bleeding using the TIMI (thrombolysis in myocardial infarction) scale. The index procedure details, including conduit type (venous vs prosthetic), were collected at baseline.
RESULTS
Among 6564 randomized patients, 2185 (33%) had undergone surgical LER. Of these 2185 patients, surgical bypass had been performed for 1448 (66%), using a prosthetic conduit for 773 patients (53%) and venous conduit for 646 patients (45%). Adjusting for the baseline differences and anatomic factors, the risk of unplanned limb revascularization in the placebo arm was 2.5-fold higher for those receiving a prosthetic conduit vs a venous conduit (adjusted hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.65-3.90; P < .001), and the risk of acute limb ischemia was three times greater (adjusted HR, 3.07; 95% CI, 1.84-5.11; P < .001). The use of rivaroxaban reduced the primary outcome for the patients treated with bypass surgery (HR, 0.78; 95% CI, 0.62-0.98), with consistent benefits for those receiving venous (HR, 0.66; 95% CI, 0.49-0.96) and prosthetic (HR, 0.87; 95% CI, 0.66-1.15) conduits (P = .254). In the overall trial, major bleeding using the TIMI scale was increased with rivaroxaban. However, the numbers for those treated with bypass surgery were low (five with rivaroxaban vs nine with placebo; HR, 0.55; 95% CI, 0.18-1.65) and not powered to show statistical significance.
CONCLUSIONS
Surgical bypass with a prosthetic conduit was associated with significantly higher rates of major adverse limb events relative to venous conduits even after adjustment for patient and anatomic characteristics. Adding rivaroxaban 2.5 mg twice daily to aspirin or dual antiplatelet therapy significantly reduced this risk, with an increase in the bleeding risk, but had a favorable benefit risk for patients treated with bypass surgery, regardless of conduit type. Rivaroxaban should be considered after lower extremity bypass for symptomatic PAD to reduce ischemic complications of the heart, limb, and brain.
Topics: Humans; Rivaroxaban; Platelet Aggregation Inhibitors; Aspirin; Peripheral Arterial Disease; Hemorrhage; Myocardial Infarction; Ischemia; Lower Extremity; Treatment Outcome
PubMed: 36470531
DOI: 10.1016/j.jvs.2022.11.062 -
Stem Cell Research & Therapy Aug 2022Critical limb ischemia (CLI) is the most severe form of peripheral artery disease and exhibits a high risk of lower extremity amputations. As even the most promising...
BACKGROUND
Critical limb ischemia (CLI) is the most severe form of peripheral artery disease and exhibits a high risk of lower extremity amputations. As even the most promising experimental approaches based on mesenchymal stem cells (MSCs) demonstrated only moderate therapeutic effects, we hypothesized that other cell types with intrinsic roles in angiogenesis may exhibit a stronger therapeutic potential. We have previously established a protocol to source human peripheral blood-derived angiogenic cells (BDACs). These cells promoted revascularization and took perivascular location at sites of angiogenesis, thus resembling hematopoietic pericytes, which were only described in vivo so far. We thus hypothesized that BDACs might have a superior ability to promote revascularization and rescue the affected limb in CLI.
METHODS
As standard BDAC sourcing techniques involve the use of animal-derived serum, we sought to establish a xeno- and/or serum-free protocol. Next, BDACs or MSCs were injected intramuscularly following the ligation of the iliac artery in a murine model. Their ability to enhance revascularization, impair necrosis and modulate inflammatory processes in the affected limb was investigated. Lastly, the secretomes of both cell types were compared to find potential indications for the observed differences in angiogenic potential.
RESULTS
From the various commercial media tested, one xeno-free medium enabled the derivation of cells that resembled functional BDACs in comparable numbers. When applied to a murine model of CLI, both cell types enhanced limb reperfusion and reduced necrosis, with BDACs being twice as effective as MSCs. This was also reflected in histological evaluation, where BDAC-treated animals exhibited the least muscle tissue degeneration. The BDAC secretome was enriched in a larger number of proteins with pro-angiogenic and anti-inflammatory properties, suggesting that the combination of those factors may be responsible for the superior therapeutic effect.
CONCLUSIONS
Functional BDACs can be sourced under xeno-free conditions paving the way for their safe clinical application. Since BDACs are derived from an easily accessible and renewable tissue, can be sourced in clinically relevant numbers and time frame and exceeded traditional MSCs in their therapeutic potential, they may represent an advantageous cell type for the treatment of CLI and other ischemic diseases.
Topics: Animals; Chronic Limb-Threatening Ischemia; Disease Models, Animal; Humans; Ischemia; Mice; Necrosis; Neovascularization, Pathologic; Neovascularization, Physiologic
PubMed: 35964057
DOI: 10.1186/s13287-022-03095-5