A review of current status of cell-based therapies for aortic aneurysms
Inflammation and Regeneration volume 43, Article number: 40 (2023)
An aortic aneurysm (AA) is defined as focal aortic dilation that occurs mainly with older age and with chronic inflammation associated with atherosclerosis. The aneurysmal wall is a complex inflammatory environment characterized by endothelial dysfunction, macrophage activation, vascular smooth muscle cell (VSMC) apoptosis, and the production of proinflammatory molecules and matrix metalloproteases (MMPs) secreted by infiltrated inflammatory cells such as macrophages, T and B cells, dendritic cells, neutrophils, mast cells, and natural killer cells. To date, a considerable number of studies have been conducted on stem cell research, and growing evidence indicates that inflammation and tissue repair can be controlled through the functions of stem/progenitor cells. This review summarizes current cell-based therapies for AA, involving mesenchymal stem cells, VSMCs, multilineage-differentiating stress-enduring cells, and anti-inflammatory M2 macrophages. These cells produce beneficial outcomes in AA treatment by modulating the inflammatory environment, including decreasing the activity of proinflammatory molecules and MMPs, increasing anti-inflammatory molecules, modulating VSMC phenotypes, and preserving elastin. This article also describes detailed studies on pathophysiological mechanisms and the current progress of clinical trials.
An aortic aneurysm (AA) is defined as the focal dilation of the aorta and occurs mainly due to aging and to chronic inflammation associated with atherosclerosis [1,2,3,4,5]. To prevent rupture, surgical interventions such as prosthetic graft replacement are required in cases with an abdominal aortic diameter over 55 mm or a thoracic aortic diameter over 60 mm or if the aortic diameter expands by more than 5 mm in the course of 6 months . Open surgical management of thoracic and thoracoabdominal AA is the standard treatment to prevent rupture. However, it is extremely invasive and is associated with high mortality and morbidity rates, especially in the elderly [7, 8]. Catheter-based interventions, namely abdominal and thoracic endovascular aneurysm repair (EVAR and TEVAR, respectively), are now widely used and are less invasive than open surgery. On the other hand, disadvantages include anatomical restriction, endoleaks, and graft migrations [9,10,11,12]. Thus, alternative strategies with reduced invasiveness are required.
Pathophysiology of AA
The aorta consists of three layers, specifically the intima, media, and adventitia. The most abundant elastic fibers in the media are produced by VSMCs and are responsible for the viscoelastic properties of the aorta that enable stretch at low pressure . Endothelial dysfunction is observed in the early stage of atherosclerosis, and it induces the infiltration of monocytes and leukocytes through monocyte chemoattractant protein-1 (MCP-1) and interleukin (IL)-8, which are secreted by injured endothelial cells (ECs) . Leukocytes infiltrate the aortic media and promote macrophage activation, regulation of VSMC apoptosis, and production of proinflammatory molecules by cytokines such as T-helper (Th) 1 cytokines (IL-2, interferon (IFN)-γ, and tumor necrosis factor (TNF)) and Th2 cytokines (IL-4, IL-5, IL-6, and IL-10). These cytokines are produced by CD4+ T cells, the most abundant type of T cell at the injury site [15, 16]. Activated macrophages play a vital role in the process of AA formation by secreting inflammatory cytokines, chemokines, and matrix metalloproteases (MMPs), especially MMP-9, which degrades elastic fibers . The production of MMP-2 by VSMCs is upregulated in vascular diseases such as atherosclerosis and also contributes to the fragmentation of elastic fibers . AA development and progression are directly associated with the lack of elastin, which plays an important role in maintaining the mechanical strength of the arterial wall. Furthermore, VSMC phenotypic switching and apoptosis are observed during AA development and result in weakening of the aortic wall . Collagen is another component of the aortic extracellular matrix (ECM) and provides resistance to stretching at high pressure . Recent findings showed that the loss of collagen type 1 significantly contributes to AA pathogenesis and is thought to lead to eventual AA rupture . In addition, the elastin/collagen ratio is significantly lower in non-aneurysmal abdominal aortas compared to AA . Meanwhile, the aneurysmal wall containing perivascular adipose tissue contains not only macrophages but also a variety of inflammatory cells such as dendritic cells (DCs), neutrophils, mast cells, natural killer (NK) cells, and B cells . It has been reported that DCs promote the activation of CD8+ T cells, NK cells, and Th1 cells via IL-12, IL-18, and IFNs produced by DCs [22, 23]. Neutrophil extracellular traps (NETs) can induce Th17-cell differentiation by increasing the transcription of IL-6 and IL-1β in macrophages . B cells differentiate into plasma cells when stimulated by IL-4 from Th cells, and immunoglobulin E (IgE) presented by plasma cells promotes macrophage polarization and mast cell activation, both of which lead to the synthesis of various proteases such as tryptases, chymases, and cathepsins [25, 26]. In addition, NK cells cause aortic wall damage by increasing MMP levels in VSMCs and macrophages and reducing VSMC viability, thereby contributing to AA development [27,28,29]. The interaction between these factors forms a complex inflammatory microenvironment and leads to AA progression [26, 30]. Controlling this environment might be a viable therapeutic strategy to treat AA. Growing evidence in stem cell research indicates that stem/progenitor cells control immunomodulation and the inflammatory response and influence tissue repair after organ injury. This review summarizes recent reports of cell-based therapies targeting the inflammatory environment during AA development and progression.
The first cell-based therapy, reported in the 1950s , was bone marrow transplantation to treat blood diseases. Reznikoff et al. established C3H mouse embryo cells in the 1970s , and then, Caplan defined a pluripotent progenitor cell called the mesenchymal stem cell (MSC), isolated from either embryos or adults, which led to the emergence of a new therapeutic self-cell repair technology . Evans et al. discovered in 1981 that pluripotent embryonic stem (ES) cells were present in the mouse embryo until the early post-implantation stage . However, ES cell research and the application of cloning technology to humans are regulated internationally for bioethical reasons . In contrast, induced pluripotent stem (iPS) cells can be directly generated from fibroblast cultures by the addition of only a few defined factors, and they exhibit the morphology and growth properties of ES cells and express ES cell marker genes . Since the ethical issues associated with ES cells do not apply to iPS cells, there have been or will soon be clinical trials using iPS cell-based therapy for diseases such as Parkinson’s disease, macular degeneration, retinitis pigmentosa, heart failure, spinal cord injury, and type 1 diabetes. Regarding cell-based therapy using MSCs, 56 phase 3 or 4 clinical trials for diseases such as myocardial infarction, rheumatoid arthritis, spinal cord injury, knee osteoarthritis, Crohn’s disease, and Covid-19 are recruiting, active, terminated, or completed according to the US National Institute of Health-ClinicalTrials database (https://clinicaltrials.gov). Prochymal®, which is a formulation of allogeneic human MSCs derived from the bone marrow of healthy adult donors, is the first stem cell drug for the treatment of acute graft-versus-host disease (GVHD) in children and was approved by Canada in 2012. Temcell® HS also consists of allogeneic human bone marrow-derived MSCs and was approved in 2015 in Japan as a new treatment option for acute steroid-refractory GVHD. Thus, cell-based therapy is expected to be a next-generation treatment that restores tissues and organs damaged by injury or disease.
Cell sources for AA cell-based therapies in AA animal models
Several studies have reported cell-based AA therapies using several types of cells, such as MSCs, smooth muscle cells (SMCs), multilineage-differentiating stress-enduring (Muse) cells, and anti-inflammatory M2 macrophages (Table 1). These cell sources are implicated in the interactions between infiltrated cells such as immune cells forming the inflammatory microenvironment of aortic aneurysmal walls (Fig. 1).
MSCs are adult somatic stem cells that can be obtained from adult tissues such as bone marrow, adipose tissue, umbilical cord, and others. MSCs are widely used as a cell source for regenerative tissue repair due to their anti-inflammatory functions and paracrine and immunomodulatory effects [50, 51]. Most reported MSC transplantation procedures have employed intravenous injection, while others have used intraperitoneal injection, catheters, and scaffolds seeded with cells. From one to four million MSCs per animal have been transplanted into mice, rats, and pigs with model AA induced by elastase, collagenase, calcium chloride, or angiotensin II. Umbilical cord-derived MSCs (UC-MSCs) were used to treat thoracic AA (TAA) and decreased the levels of IL-27 and chemokines such as CXCL13, CXCL12, and CCL5 at day 14 in mice perfused with elastase . Several papers demonstrated that transplantation of bone marrow-derived MSCs (BM-MSCs) inhibited AA development and growth by attenuating MMP-2 and MMP-9 expression, reducing ECM degradation, and decreasing the levels of proinflammatory cytokines such as TNF-α, IL-1β, IL-6, and MCP-1 [37, 38, 40]. Interestingly, BM-MSCs derived from female mice were more effective than those from male mice in attenuating abdominal AA (AAA) growth and decreasing levels of proinflammatory cytokines, particularly IL-17, in a murine model . The superior therapeutic efficacy of female BM-MSCs was also observed in the context of myocardial function following ischemia-reperfusion injury . This suggests that compared to male BM-MSCs, female stem cells may have more greatly enhanced resistance to injury or insult due to higher expression of vascular endothelial growth factor (VEGF) and lower expression of TNF-α. There are also several reports on anti-inflammatory effects and factors related to the ECM. Zilberman et al. reported that pigs treated with adipose-derived MSCs (AD-MSCs) exhibited increased expression of VEGF, tissue inhibitor of matrix metalloproteinase (TIMP)-1, and TIMP-3 in elastase and collagenase-perfused aortas at day 21 after surgery, resulting in a 33% narrower aorta than in untreated pigs, due to the preservation of ECM components . Another report showed upregulation of aortic TIMP-1 28 days after infusion of angiotensin II in apolipoprotein E-deficient mice . Autologous BM-MSC-treated AA mice also exhibited increased expression of IL-10, TIMP-2, and insulin-like growth factor (IGF)-1 in AA tissue, and similar results were obtained with allogeneic BM-MSC-treated mice [44, 46, 53]. Notably, BM-MSC administration to mice with already-formed AA induced aortic reverse remodeling through regulation of pro- and anti-inflammatory factors, including those mentioned above .
VSMCs, SPCs, and iPS-SMP cells
Degradation of elastin fiber in the aortic media contributes to aortic expansion. IGF-1, which is a potent elastogenic stimulator, is secreted by MSCs and induces elastin production in cultures of human aortic SMCs . Co-culture of SMCs and AD-MSCs was shown to promote elastin secretion from SMCs, suggesting that secreted elastin contributes to the reconstruction of elastic fibers in AA tissue . In addition, AD-MSCs can modulate the restoration and/or preservation of the contractile phenotype of VSMCs. Wen et al. demonstrated that the expression levels of two VSMC contractile markers, namely smooth muscle actin (SMA)-α and smooth muscle (SM)-22, were effectively restored in the medial wall of abdominal aortas on day 14 after UC-MSC administration . These reports suggest that modulation of SMC phenotypes is important for AA development and enlargement. Thus, it is reasonable to hypothesize that highly elastogenic SMCs may be useful as a cell source for cell-based AA therapy. In an attempt to directly deliver therapeutic cells to the peri-adventitia of murine aneurysms, Mulorz et al. implanted porous collagen scaffolds seeded with either primary human aortic SMCs or induced pluripotent stem cell-derived-smooth muscle progenitor cells (iPSC-SMPs) . They showed that 28 days after implantation, SMC-seeded scaffolds significantly reduced the aortic diameter compared to scaffolds seeded with iPSC-SMPs or no cells. In addition, the SMC-seeded scaffolds exhibited more SMC retention and less macrophage invasion into the medial layer of AAA lesions compared to scaffolds not seeded with cells. Chen et al. demonstrated that subadventitial injection of lysyl oxidase (LOX) gene-modified autologous smooth muscle progenitor cells (SPCs) enhanced elastin synthesis, increased preservation of elastic laminar integrity, improved SPC survival, and restored the SMC population, thereby attenuating aortic expansion in rabbit AAA . On the other hand, Schneider et al. compared the effects of BM-MSCs and SMCs and suggested that endovascular seeding of BM-MSCs decreased AAA diameter expansion more potently than that of vascular SMCs . Through paracrine mechanisms, MSC seeding resulted in the accumulation of SMC-like cells surrounded by ECM with dense collagen and elastin, thus inducing aortic healing.
There have been recent advances in the development of human bone marrow-derived Muse cells, which are known to be endogenous, non-tumorigenic, pluripotent-like stem cells that are a potent cell source for AA therapy [42, 55]. Intravenously injected Muse cells homed into the AA from the adventitial side and then infiltrated the aortic tissue in a murine AA model induced by calcium chloride and collagenase and then differentiated spontaneously into VSMCs and ECs, resulting in attenuation of aortic dilation . Although Muse cells may be a promising cell source, they comprise only about 0.03% of the mononucleated fraction in bone marrow. Established cell culture methods are needed to ensure a sufficient number of cells for treatment.
Anti-inflammatory M2 macrophages
Circulating monocytes in blood can be recruited to tissues with inflammatory changes in the local environment, where they differentiate into distinct macrophage phenotypes, including classically activated inflammatory M1 macrophages and alternatively activated anti-inflammatory M2 macrophages . Anti-inflammatory M2 macrophages have unique properties such as the ability to inhibit inflammation and accelerate tissue remodeling [57, 58], suggesting that they might also be useful for AA treatment. Promising outcomes of the first investigation into the utility of M2 macrophages for AA were recently published. Ashida et al. demonstrated that M2 macrophages differentiated from the J774A.1 commercial cell line using IL-4, IL-10, and TGF-β1 and inhibited AA expansion after injection into mice by improving the balance between inflammation and anti-inflammation . Their findings are somewhat inconclusive, however, because the macrophages in their study were derived from a commercial cell line, and induced M2 macrophages might switch phenotype. However, it is advantageous that macrophages can be easily obtained from mononuclear cells in blood rather than from MSCs and are expected to be a new cell source for AA therapy.
Pathophysiological mechanisms of AA treatment with MSCs
Cell interaction and signaling pathways
Many types of immune cells, including macrophages, T cells, B cells, neutrophils, DCs, mast cells, and NK cells, have been observed infiltrating the aortic wall and are thus thought to play crucial roles in AA pathophysiology . Understanding the interactions between immune cells and therapeutic cells in cell-based therapies is important for clarifying the treatment mechanisms. The roles of MSCs against macrophages, T cells, and neutrophils in the aortic wall and the circulation have been investigated in several studies. Intravenous injection of MSCs increased the numbers of aortic regulatory T cells (Tregs; by 20-fold) and CD206+ M2 macrophages and decreased the numbers of aortic CD4+CD28− T cells, CD8+CD28− T cells, and Ly6G/C+ neutrophils, as well as circulating CD115+CXCR1−LY6C+ activated monocytes . In addition, although AA infiltration of dominant M1 macrophages and recessive M2 macrophages has been observed, MSCs modulate the M1/M2 macrophage ratio in AA [53, 59, 60]. These data suggest that communication between MSCs and immune cells exerts paracrine effects both locally and systemically.
Macrophage-produced high mobility group box 1 (HMGB1), a damage-associated molecular pattern molecule whose production is enhanced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, activates IL-17 production from CD4+ T cells and vascular inflammation . Sharma et al. found that MSCs suppressed macrophages and CD4+ T-cell activation, which attenuated IL-17 and HMGB1 production and led to decreased inflammation and vascular remodeling in experimental AA mice . They suggested that the mechanistic signaling pathway of MSC-mediated protection targets the NADPH oxidase 2 pathway. Other reported signaling pathways in AA include the activation of c-Jun N-terminal kinase (JNK), nuclear factor-kappa B (NF-kB), signal transducer and activator of transcription (STAT), extracellular signal-regulated kinase (ERK), and Sma- and Mad-related protein (Smad) pathways and the reduction of protein kinase B (Akt). A recent study showed that administration of MSCs contributed to the regulation of the NF-κB, Smad3, and Akt signaling pathways . The same paper also investigated trophic proteins in conditioned medium derived from MSCs. The authors identified several secreted factors, including activin A, IGF-1, IGF-binding protein (IGFBP)-1, NF-κB repressing factor (NRF), and platelet-derived growth factor (PDGF)-AA, and suggested that NRF and IGFBP-3 might promote downregulation of NF-κB and that PDGF-AA and activin A might induce upregulation of Akt and Smad3.
Mediatory role of microRNA
There is growing interest in microRNA (miRNA), and a number of studies have attempted to identify miRNA expression patterns that contribute to AA. A review paper showed that miR-155 and miR-29b in both aortic tissue and circulating blood were associated with human AAA . The target genes of miR-155 are cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and Smad2, and significant downregulation of miR-155 in AAA compared to the AAA neck was identified. Overexpression of miR-155 was also observed in model mice with AA induced by angiotensin II . This study demonstrated that miR-155 overexpression enhanced the levels of MMP-2, MMP-9, inducible nitric oxide synthase (iNOS), and MCP-1 and stimulated the proliferation and migration of VSMCs . Recent work has revealed that miR-155 promotes the development of inflammatory T cells, including Th17 and Th1 subsets, and plays a critical role in CD4+ T-cell differentiation, activation, function, and apoptosis [66, 67]. In in vitro assays, MSC-secreted TGF-β1 inhibited the expression of miR-155 on CD4+ T cells treated with LPS and hypoxia . The role of miR-155 in AA mice treated with MSCs remains unclear and requires further investigation.
A decreased level of miR-29b in AA was identified in human and experimental animals [44, 69, 70]. It was reported that miR-29b regulates collagen deposition and fibrosis through its targets, namely collagen type 1 α1 (COL1A1), COL3A1, COL5A1, and elastin . Hawkins et al. investigated changes in miRNA expression profiles in experimental TAA after treatment with or without MSCs . Differential expression of 53 miRNAs was identified between elastase-induced TAA and sham. Specifically, miR-146a and miR-21 were upregulated, while miR-27b, miR29b, and miR-29c were downregulated. High expression of miR-146a and miR-21 was also reported in patients with AAA and in experimental AA [44, 69, 71, 72]. These miRNAs are associated with leukocyte infiltration, aortic inflammation, and loss of smooth muscle cell activation, which together lead to vascular remodeling and TAA formation. On the other hand, treatment of TAA with MSCs led to upregulation of miR-24, miR-29b, and miR-10a compared to non-treated TAA . It was reported that miR-24 plays a key role in regulating vascular inflammation by promoting aortic smooth muscle cell migration and stimulating adhesion molecule expression in vascular ECs . In addition, miR-29b, which is upregulated in VSMCs treated with PDGF-BB, regulates the transformation of VSMC phenotypes . miR-10a, which exhibits low expression in the athero-susceptible regions of the endothelium, contributes to the regulation of proinflammatory endothelial phenotypes .
Recently, it has become clear that extracellular vesicles (EVs) consisting of exosomes and microvesicles (MVs) play a role in cell-cell communication. These structures are secreted by cells and contain proteins, lipids, and genetic material such as messenger ribonucleic acid (mRNA) and miRNA, which are transferred to target cells. The functions of EVs contribute to the complex paracrine effects of MSC therapy. Spinosa et al. reported that during AAA formation, MSC-derived MVs played a critical role in attenuating inflammation and macrophage activation via miR-147, a key mediator of macrophage inflammatory responses . On the other hand, administration of MSC-derived exosomes inhibited the expansion of the aortic diameter in existing AA, and highly expressed miRNAs such as miR-21, the miR-23/24/27 family, miR-92, miR-143, miR-145, and miR-221 were identified in MSC-derived exosomes. Further investigation of the mediatory role of miRNAs, one of the multifunctional effects of MSCs, may help clarify the mechanisms of MSCs-based therapy in AA.
Paracrine effects of trophic factors secreted by MSCs
Conditioned medium derived from MSCs contains numerous secreted factors that contribute to regulating the inflammatory response, immunomodulation, and ECM synthesis. In vitro studies have investigated changes in the expression of macrophage-secreted factors when macrophages and MSCs are co-cultured in a transwell system. Treatment of inflammatory macrophages with liposaccharide promoted their secretion of inflammatory cytokines, chemokines, and MMPs such as IL-1β, IL-6, TNF-α, MCP-1, MMP-2, and MMP-9, whereas MSCs led to decreased secretion of these compounds from both inflammatory macrophages and unstimulated macrophages [37, 60]. In parallel, macrophages co-cultured with MSCs promoted IL-10 production by macrophages and induced higher gene expression of CD206, Arginase-1, and Ym-1, all of which are M2 macrophage-specific markers . In VSMCs co-cultured with MSCs, gene expression of elastin was upregulated compared with VSMC monoculture . The immune cells that most predominantly infiltrate AA lesions are CD4+ T cells, especially Th1, Th2, Th17, and Th22 subsets . The proliferation, activation, and differentiation of CD4+ T cells induced to differentiate into Th1 and Th17 cells are suppressed by MSC co-culture, thereby contributing to increases in both IL-10 secretion and the percentage of functional-induced regulatory T cells . Zhou et al. showed that administration of MSC-derived conditioned medium to mice had similar effects as MSC administration, including inhibition of AA growth, prevention of elastin degradation, attenuation of MMP expression, and decreased expression of proinflammatory cytokines, suggesting that utilizing MSC-derived conditioned medium might be a novel cell‐free therapeutic approach for AA .
In a more recent study, Wang et al. showed that exosomes from inflammatory macrophages facilitated MMP-2 production by VSMCs via JNK and p38 pathways in vitro . In addition, intraperitoneal injection of GW4869, an inhibitor of exosome biogenesis, attenuated the progression of calcium phosphate-induced AAA by preserving elastin integrity and decreasing MMP-2 expression. Interestingly, one study compared proteolytic activity and elastin deposition in VSMCs cultured with MSC-derived exosomes, conditioned medium including exosomes, and conditioned medium excluding exosomes . A critical finding was that exosome injection had superior effects to conditioned medium with or without exosomes. This report showed that MSC-derived exosomes reduced the expression of elastolytic MMP2, significantly decreased the MMP2/TIMP2 ratio, and enhanced elastin matrix deposition and elevated lox expression in AAA-SMCs. Therefore, MSC-derived exosomes are important for their elastic matrix regenerative and anti-proteolytic properties. These reports are of enormous interest as they suggest a possible alternative to cell-based therapy that would avoid MSC-related issues related to cell-based therapy such as cell origin, quality, functionality requirements for MSC production, and immunocompatibility.
According to the US National Institute of Health-ClinicalTrials database (https://clinicaltrials.gov), there are 621 clinical trials involving MSCs as cell-based therapy. These trials are at various stages, specifically recruiting, active non-recruiting, terminated, and completed. Clinical studies on the use of MSCs have been reported in various conditions, including the following: cardiovascular diseases; GVHD; brain and neurological disorders; bone, joint, and muscle disorders; lung and bronchial diseases; wounds and restoration; and Covid-19. Studies of complex perianal fistulas in patients with Crohn’s disease and those with phase 3 GVHD reported that MSC-based therapy was effective and safe [81, 82]. Regarding AA, a phase 1 (NCT02846883), single-center, double-blind, randomized controlled trial was performed to investigate the safety of MSC infusion for patients with small AAA . The aim of this study was to assess the safety of intravenous MSC injection at doses of 1 million or 3 million MSCs/kg and changes in aortic inflammation as measured by 18-fluorodeoxyglucose positron emission tomography/computed tomography. The status of this study is “terminated,” but the data are still being evaluated.
We reviewed the current state of cell-based therapies for treatment of AA in animal and clinical studies. Several types of cells, including MSCs isolated from bone marrow, adipose tissue, and umbilical cord, as well as VSMCs, mononuclear cell-derived SPCs, iPS-SMP cells, Muse cells, and M2 macrophages, have been used as cell sources and have been shown to inhibit AA development and growth by modulating inflammatory responses and preserving and/or restoring the VSMC contractile phenotype in experimental AA. Moreover, reverse remodeling of the aorta after AA growth in mice was induced by MSC therapy. Studies utilizing MSCs to treat AA have become more common in recent years, and the therapeutic mechanism is becoming clearer. The use of MSC-derived EVs may be beneficial as they carry no risk of the thromboembolism associated with MSC transplants. Although animal studies cannot perfectly mimic the pathogenesis of AA in humans, cell-based therapies have potential as minimally invasive AA treatments. Safety evaluations are being performed in phase 1 clinical studies, and the outcomes will serve as the cornerstone of future research on nonsurgical AA treatment.
Availability of data and materials
Abdominal aortic aneurysm
Adipose-derived mesenchymal stem cells
Protein kinase B
α-Smooth muscle actin
Bone marrow-derived mesenchymal stem cells
Cytotoxic T-lymphocyte-associated protein 4
Endovascular aneurysm repair
Extracellular signal-regulated kinase
High mobility group box 1
Insulin-like growth factor-1
Insulin-like growth factor binding protein-1
Inducible nitric oxide synthase
Induced pluripotent stem cell
Induced pluripotent stem cell-derived smooth muscle progenitor cells
c-Jun N-terminal kinase
Monocyte chemoattractant protein-1
Messenger ribonucleic acid
Mesenchymal stem cells
- Muse cells:
Multilineage-differentiating stress-enduring cells
Nicotinamide adenine dinucleotide phosphate
Neutrophil extracellular traps
- NK cells:
Natural killer cells
Nuclear factor-kappa B
NF-κB repressing factor
Platelet-derived growth factor
Smooth muscle cells
Sma- and Mad-related proteins
Smooth muscle progenitor cells
Signal transducer and activator of transcription
Thoracic aortic aneurysm
Thoracic endovascular aneurysm repair
Transforming growth factor-β1
Tissue inhibitor matrix metalloproteinase
Tumor necrosis factor-α
Regulatory T cells
Umbilical cord-derived mesenchymal stem cells
Vascular endothelial growth factor
Vascular smooth muscle cells
Johnston KW, Rutherford RB, Tilson MD, Shah DM, Hollier L, Stanley JC. Suggested standards for reporting on arterial aneurysms. Subcommittee on reporting standards for arterial aneurysms, ad hoc committee on reporting standards, Society for Vascular Surgery and North American Chapter, International Society for Cardiovascular Surgery. J Vasc Surg. 1991;13(3):452–8.
Iribarren C, Darbinian JA, Go AS, Fireman BH, Lee CD, Grey DP. Traditional and novel risk factors for clinically diagnosed abdominal aortic aneurysm: the Kaiser multiphasic health checkup cohort study. Ann Epidemiol. 2007;17(9):669–78.
LeFevre ML. Force USPST: screening for abdominal aortic aneurysm: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;161(4):281–90.
AAASG International, Bjorck M, Bown MJ, Choke E, Earnshaw J, Florenes T, et al. International update on screening for abdominal aortic aneurysms: issues and opportunities. Eur J Vasc Endovasc Surg. 2015;49(2):113–5.
Kent KC, Zwolak RM, Egorova NN, Riles TS, Manganaro A, Moskowitz AJ, et al. Analysis of risk factors for abdominal aortic aneurysm in a cohort of more than 3 million individuals. J Vasc Surg. 2010;52(3):539–48.
JCSJW Group. Guidelines for diagnosis and treatment of aortic aneurysm and aortic dissection (JCS 2011): digest version. Circ J. 2013;77(3):789–828.
Shiiya N, Washiyama N, Tsuda K, Yamanaka K, Takahashi D, Yamashita K, et al. Japanese perspective in surgery for thoracoabdominal aortic aneurysms. Gen Thorac Cardiovasc Surg. 2019;67(1):187–91.
Coselli JS, LeMaire SA, Preventza O, de la Cruz KI, Cooley DA, Price MD, et al. Outcomes of 3309 thoracoabdominal aortic aneurysm repairs. J Thorac Cardiovasc Surg. 2016;151(5):1323–37.
Verzini F, Cieri E, Kahlberg A, Sternbach Y, Heijmen R, Ouriel K, et al. A preliminary analysis of late structural failures of the Navion stent graft in the treatment of descending thoracic aortic aneurysms. J Vasc Surg. 2021;74(4):1125-34 e2.
Kouvelos GN, Spanos K, Nana P, Koutsias S, Rousas N, Giannoukas A, et al. Large diameter (>/=29 mm) proximal aortic necks are associated with increased complication rates after endovascular repair for abdominal aortic aneurysm. Ann Vasc Surg. 2019;60:70–5.
Oliveira NFG, Goncalves FB, Ultee K, Pinto JP, Josee van Rijn M, Raa ST, et al. Patients with large neck diameter have a higher risk of type IA endoleaks and aneurysm rupture after standard endovascular aneurysm repair. J Vasc Surg. 2019;69(3):783–91.
McFarland G, Tran K, Virgin-Downey W, Sgroi MD, Chandra V, Mell MW, et al. Infrarenal endovascular aneurysm repair with large device (34- to 36-mm) diameters is associated with higher risk of proximal fixation failure. J Vasc Surg. 2019;69(2):385–93.
Kim J, Staiculescu MC, Cocciolone AJ, Yanagisawa H, Mecham RP, Wagenseil JE. Crosslinked elastic fibers are necessary for low energy loss in the ascending aorta. J Biomech. 2017;61:199–207.
Poddar R, Sivasubramanian N, DiBello PM, Robinson K, Jacobsen DW. Homocysteine induces expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human aortic endothelial cells: implications for vascular disease. Circulation. 2001;103(22):2717–23.
Sprague AH, Khalil RA. Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol. 2009;78(6):539–52.
Sagan A, Mikolajczyk TP, Mrowiecki W, MacRitchie N, Daly K, Meldrum A, et al. T cells are dominant population in human abdominal aortic aneurysms and their infiltration in the perivascular tissue correlates with disease severity. Front Immunol. 2019;10:1979.
Chen Q, Jin M, Yang F, Zhu J, Xiao Q, Zhang L. Matrix metalloproteinases: inflammatory regulators of cell behaviors in vascular formation and remodeling. Mediators Inflamm. 2013;2013: 928315.
Xue M, Li G, Li D, Wang Z, Mi L, Da J et al: Up-regulated MCPIP1 in abdominal aortic aneurysm is associated with vascular smooth muscle cell apoptosis and MMPs production. Biosci Rep 2019;39(11).
Quintana RA, Taylor WR. Cellular mechanisms of aortic aneurysm formation. Circ Res. 2019;124(4):607–18.
Cho BS, Roelofs KJ, Ford JW, Henke PK, Upchurch GR Jr. Decreased collagen and increased matrix metalloproteinase-13 in experimental abdominal aortic aneurysms in males compared with females. Surgery. 2010;147(2):258–67.
He CM, Roach MR. The composition and mechanical properties of abdominal aortic aneurysms. J Vasc Surg. 1994;20(1):6–13.
Yan H, Zhou HF, Akk A, Hu Y, Springer LE, Ennis TL, et al. Neutrophil proteases promote experimental abdominal aortic aneurysm via extracellular trap release and plasmacytoid dendritic cell activation. Arterioscler Thromb Vasc Biol. 2016;36(8):1660–9.
Miossec P. Dynamic interactions between T cells and dendritic cells and their derived cytokines/chemokines in the rheumatoid synovium. Arthritis Res Ther. 2008;10 Suppl 1(Suppl 1):S2.
Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol. 2018;18(2):134–47.
Zhang X, Li J, Luo S, Wang M, Huang Q, Deng Z, et al. IgE contributes to atherosclerosis and obesity by affecting macrophage polarization, macrophage protein network, and foam cell formation. Arterioscler Thromb Vasc Biol. 2020;40(3):597–610.
Yuan Z, Lu Y, Wei J, Wu J, Yang J, Cai Z. Abdominal aortic aneurysm: roles of inflammatory cells. Front Immunol. 2020;11: 609161.
van Puijvelde GHM, Foks AC, van Bochove RE, Bot I, Habets KLL, de Jager SC, et al. CD1d deficiency inhibits the development of abdominal aortic aneurysms in LDL receptor deficient mice. PLoS One. 2018;13(1): e0190962.
Sasaguri T, Arima N, Tanimoto A, Shimajiri S, Hamada T, Sasaguri Y. A role for interleukin 4 in production of matrix metalloproteinase 1 by human aortic smooth muscle cells. Atherosclerosis. 1998;138(2):247–53.
Chizzolini C, Rezzonico R, De Luca C, Burger D, Dayer JM. Th2 cell membrane factors in association with IL-4 enhance matrix metalloproteinase-1 (MMP-1) while decreasing MMP-9 production by granulocyte-macrophage colony-stimulating factor-differentiated human monocytes. J Immunol. 2000;164(11):5952–60.
Marquez-Sanchez AC, Koltsova EK. Immune and inflammatory mechanisms of abdominal aortic aneurysm. Front Immunol. 2022;13: 989933.
Thomas ED, Lochte HL Jr, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N Engl J Med. 1957;257(11):491–6.
Reznikoff CA, Brankow DW, Heidelberger C. Establishment and characterization of a cloned line of C3H mouse embryo cells sensitive to postconfluence inhibition of division. Cancer Res. 1973;33(12):3231–8.
Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991;9(5):641–50.
Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292(5819):154–6.
Abbott A. European embryology experts offer to advise on ethics of cloning. Nature. 1999;400(6740):103.
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.
Hashizume R, Yamawaki-Ogata A, Ueda Y, Wagner WR, Narita Y. Mesenchymal stem cells attenuate angiotensin II-induced aortic aneurysm growth in apolipoprotein E-deficient mice. J Vasc Surg. 2011;54(6):1743–52.
Fu XM, Yamawaki-Ogata A, Oshima H, Ueda Y, Usui A, Narita Y. Intravenous administration of mesenchymal stem cells prevents angiotensin II-induced aortic aneurysm formation in apolipoprotein E-deficient mouse. J Transl Med. 2013;11:175.
Schneider F, Saucy F, de Blic R, Dai J, Mohand F, Rouard H, et al. Bone marrow mesenchymal stem cells stabilize already-formed aortic aneurysms more efficiently than vascular smooth muscle cells in a rat model. Eur J Vasc Endovasc Surg. 2013;45(6):666–72.
Davis JP, Salmon M, Pope NH, Lu G, Su G, Sharma AK, et al. Attenuation of aortic aneurysms with stem cells from different genders. J Surg Res. 2015;199(1):249–58.
Tian X, Fan J, Yu M, Zhao Y, Fang Y, Bai S, et al. Adipose stem cells promote smooth muscle cells to secrete elastin in rat abdominal aortic aneurysm. PLoS One. 2014;9(9): e108105.
Hosoyama K, Wakao S, Kushida Y, Ogura F, Maeda K, Adachi O, et al. Intravenously injected human multilineage-differentiating stress-enduring cells selectively engraft into mouse aortic aneurysms and attenuate dilatation by differentiating into multiple cell types. J Thorac Cardiovasc Surg. 2018;155(6):2301-13 e4.
Chen F, Zhang Z, Zhu X. Inhibition of development of experimental abdominal aortic aneurysm by c-jun N-terminal protein kinase inhibitor combined with lysyl oxidase gene modified smooth muscle progenitor cells. Eur J Pharmacol. 2015;766:114–21.
Hawkins RB, Salmon M, Su G, Lu G, Leroy V, Bontha SV, et al. Mesenchymal stem cells alter MicroRNA expression and attenuate thoracic aortic aneurysm formation. J Surg Res. 2021;268:221–31.
Wen H, Wang M, Gong S, Li X, Meng J, Wen J, et al. Human umbilical cord mesenchymal stem cells attenuate abdominal aortic aneurysm progression in sprague-dawley rats: implication of vascular smooth muscle cell phenotypic modulation. Stem Cells Dev. 2020;29(15):981–93.
Akita N, Narita Y, Yamawaki-Ogata A, Usui A, Komori K. Therapeutic effect of allogeneic bone marrow-derived mesenchymal stromal cells on aortic aneurysms. Cell Tissue Res. 2021;383(2):781–93.
Mulorz J, Shayan M, Hu C, Alcazar C, Chan AHP, Briggs M, et al. Peri-adventitial delivery of smooth muscle cells in porous collagen scaffolds for treatment of experimental abdominal aortic aneurysm. Biomater Sci. 2021;9(20):6903–14.
Zilberman B, Kooragayala K, Lou J, Ghobrial G, De Leo N, Emery R, et al. Treatment of abdominal aortic aneurysm utilizing adipose-derived mesenchymal stem cells in a porcine model. J Surg Res. 2022;278:247–56.
Ashida S, Yamawaki-Ogata A, Tokoro M, Mutsuga M, Usui A, Narita Y. Administration of anti-inflammatory M2 macrophages suppresses progression of angiotensin II-induced aortic aneurysm in mice. Sci Rep. 2023;13(1):1380.
Brown C, McKee C, Bakshi S, Walker K, Hakman E, Halassy S, et al. Mesenchymal stem cells: cell therapy and regeneration potential. J Tissue Eng Regen Med. 2019;13(9):1738–55.
Suman S, Domingues A, Ratajczak J, Ratajczak MZ. Potential clinical applications of stem cells in regenerative medicine. Adv Exp Med Biol. 2019;1201:1–22.
Crisostomo PR, Markel TA, Wang M, Lahm T, Lillemoe KD, Meldrum DR. In the adult mesenchymal stem cell population, source gender is a biologically relevant aspect of protective power. Surgery. 2007;142(2):215–21.
Yamawaki-Ogata A, Fu X, Hashizume R, Fujimoto KL, Araki Y, Oshima H, et al. Therapeutic potential of bone marrow-derived mesenchymal stem cells in formed aortic aneurysms of a mouse model. Eur J Cardiothorac Surg. 2014;45(5):e156-65.
Shi J, Wang A, Sen S, Wang Y, Kim HJ, Mitts TF, et al. Insulin induces production of new elastin in cultures of human aortic smooth muscle cells. Am J Pathol. 2012;180(2):715–26.
Wakao S, Akashi H, Kushida Y, Dezawa M. Muse cells, newly found non-tumorigenic pluripotent stem cells, reside in human mesenchymal tissues. Pathol Int. 2014;64(1):1–9.
Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol. 2011;11(11):750–61.
Ross EA, Devitt A, Johnson JR. Macrophages: the good, the bad, and the gluttony. Front Immunol. 2021;12: 708186.
Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5(12):953–64.
Xie J, Jones TJ, Feng D, Cook TG, Jester AA, Yi R, et al. Human adipose-derived stem cells suppress elastase-induced murine abdominal aortic inflammation and aneurysm expansion through paracrine factors. Cell Transplant. 2017;26(2):173–89.
Zhou YZ, Cheng Z, Wu Y, Wu QY, Liao XB, Zhao Y, et al. Mesenchymal stem cell-derived conditioned medium attenuate angiotensin II-induced aortic aneurysm growth by modulating macrophage polarization. J Cell Mol Med. 2019;23(12):8233–45.
Sharma AK, LaPar DJ, Stone ML, Zhao Y, Kron IL, Laubach VE. Receptor for advanced glycation end products (RAGE) on iNKT cells mediates lung ischemia-reperfusion injury. Am J Transplant. 2013;13(9):2255–67.
Sharma AK, Salmon MD, Lu G, Su G, Pope NH, Smith JR, et al. Mesenchymal stem cells attenuate NADPH oxidase-dependent high mobility group box 1 production and inhibit abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol. 2016;36(5):908–18.
Yamawaki-Ogata A, Oshima H, Usui A, Narita Y. Bone marrow-derived mesenchymal stromal cells regress aortic aneurysm via the NF-kB, Smad3 and Akt signaling pathways. Cytotherapy. 2017;19(10):1167–75.
Iyer V, Rowbotham S, Biros E, Bingley J, Golledge J. A systematic review investigating the association of microRNAs with human abdominal aortic aneurysms. Atherosclerosis. 2017;261:78–89.
Zhang Z, Liang K, Zou G, Chen X, Shi S, Wang G et al: Inhibition of miR-155 attenuates abdominal aortic aneurysm in mice by regulating macrophage-mediated inflammation. Biosci Rep 2018;38(3).
O’Connell RM, Kahn D, Gibson WS, Round JL, Scholz RL, Chaudhuri AA, et al. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity. 2010;33(4):607–19.
Chen L, Gao D, Shao Z, Zheng Q, Yu Q. miR-155 indicates the fate of CD4(+) T cells. Immunol Lett. 2020;224:40–9.
Xue M, Zhang X, Chen J, Liu F, Xu J, Xie J, et al. Mesenchymal stem cell-secreted TGF-beta1 restores Treg/Th17 skewing induced by lipopolysaccharide and hypoxia challenge via miR-155 suppression. Stem Cells Int. 2022;2022:5522828.
Kin K, Miyagawa S, Fukushima S, Shirakawa Y, Torikai K, Shimamura K, et al. Tissue- and plasma-specific MicroRNA signatures for atherosclerotic abdominal aortic aneurysm. J Am Heart Assoc. 2012;1(5): e000745.
Maegdefessel L, Azuma J, Toh R, Merk DR, Deng A, Chin JT, et al. Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development. J Clin Invest. 2012;122(2):497–506.
Liu G, Huang Y, Lu X, Lu M, Huang X, Li W, et al. Identification and characteristics of microRNAs with altered expression patterns in a rat model of abdominal aortic aneurysms. Tohoku J Exp Med. 2010;222(3):187–93.
Maegdefessel L, Azuma J, Toh R, Deng A, Merk DR, Raiesdana A, et al. MicroRNA-21 blocks abdominal aortic aneurysm development and nicotine-augmented expansion. Sci Transl Med. 2012;4(122):122ra22.
Maegdefessel L, Spin JM, Raaz U, Eken SM, Toh R, Azuma J, et al. miR-24 limits aortic vascular inflammation and murine abdominal aneurysm development. Nat Commun. 2014;5:5214.
Sun QR, Zhang X, Fang K. Phenotype of vascular smooth muscle cells (VSMCs) is regulated by miR-29b by targeting Sirtuin 1. Med Sci Monit. 2018;24:6599–607.
Fang Y, Shi C, Manduchi E, Civelek M, Davies PF. MicroRNA-10a regulation of proinflammatory phenotype in athero-susceptible endothelium in vivo and in vitro. Proc Natl Acad Sci U S A. 2010;107(30):13450–5.
Spinosa M, Lu G, Su G, Bontha SV, Gehrau R, Salmon MD, et al. Human mesenchymal stromal cell-derived extracellular vesicles attenuate aortic aneurysm formation and macrophage activation via microRNA-147. FASEB J. 2018;32(11):fg201701138RR.
Teo FH, de Oliveira RTD, Villarejos L, Mamoni RL, Altemani A, Menezes FH, et al. Characterization of CD4(+) T cell subsets in patients with abdominal aortic aneurysms. Mediators Inflamm. 2018;2018:6967310.
Luz-Crawford P, Kurte M, Bravo-Alegria J, Contreras R, Nova-Lamperti E, Tejedor G, et al. Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem Cell Res Ther. 2013;4(3):65.
Wang Y, Jia L, Xie Y, Cai Z, Liu Z, Shen J, et al. Involvement of macrophage-derived exosomes in abdominal aortic aneurysms development. Atherosclerosis. 2019;289:64–72.
Sajeesh S, Broekelman T, Mecham RP, Ramamurthi A. Stem cell derived extracellular vesicles for vascular elastic matrix regenerative repair. Acta Biomater. 2020;113:267–78.
Kurtzberg J, Abdel-Azim H, Carpenter P, Chaudhury S, Horn B, Mahadeo K, et al. a phase 3, single-arm, prospective study of remestemcel-L, ex vivo culture-expanded adult human mesenchymal stromal cells for the treatment of pediatric patients who failed to respond to steroid treatment for acute graft-versus-host disease. Biol Blood Marrow Transplant. 2020;26(5):845–54.
Panes J, Garcia-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, et al. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet. 2016;388(10051):1281–90.
Wang SK, Green LA, Gutwein AR, Drucker NA, Motaganahalli RL, Fajardo A, et al. Rationale and design of the ARREST trial investigating mesenchymal stem cells in the treatment of small abdominal aortic aneurysm. Ann Vasc Surg. 2018;47:230–7.
This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 22H03155.
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Yamawaki-Ogata, A., Mutsuga, M. & Narita, Y. A review of current status of cell-based therapies for aortic aneurysms. Inflamm Regener 43, 40 (2023). https://doi.org/10.1186/s41232-023-00280-8
- Aortic aneurysm (AA)
- Cell-based therapy
- Extracellular matrix (ECM)
- Matrix metalloproteinases (MMPs)
- Mesenchymal stem cells (MSCs)
- Smooth muscle cells (SMCs)
- MicroRNA (miRNA)