Engineering the Future of Stem Cells in Vascular
Reconstruction: A Leap Towards Functional
Endothelialized Tissue-Engineered Vascular Conduits

Haïzam Oubari, Yanis Berkane, Maxime Jeljeli, Alexandre G Lellouch, David M Smadja

► To cite this version:

Haïzam Oubari, Yanis Berkane, Maxime Jeljeli, Alexandre G Lellouch, David M Smadja. Engineering the Future of Stem Cells in Vascular Reconstruction: A Leap Towards Functional Endothelialized Tissue-Engineered Vascular Conduits. Stem Cell Reviews and Reports, 2025, 21 (8), pp.2796-2806. 10.1007/s12015-025-10968-8. hal-05298994

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Distributed under a Creative Commons Attribution 4.0 International License
# Engineering the Future of Stem Cells in Vascular Reconstruction: A Leap Towards Functional Endothelialized Tissue-Engineered Vascular Conduits

Haizam Oubari<fnref n="1" /> · Yanis Berkane<fnref n="2" />,<fnref n="3" /> · Maxime Jeljeli<fnref n="4" /> · Alexandre G. Lellouch<fnref n="4" />,<fnref n="5" />,<fnref n="6" /> · David M. Smadja<fnref n="5" />,<fnref n="6" />

Received: 1 July 2025 / Accepted: 12 August 2025

© The Author(s) 2025

## Abstract

The transition from reconstructive to regenerative strategies in vascular surgery has intensified the need for grafts that are biocompatible, growth-capable, and resistant to thrombosis. Addressing this challenge, Park et al. introduce a ground-breaking method for engineering fully biological, endothelialized tissue-engineered vascular conduits (TEVCs) using decellularized human umbilical arteries (dHUAs) coated with human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs). These constructs undergo shear stress training in bioreactors, mimicking physiological blood flow to enhance endothelial functionality and anti-thrombotic properties. Upon implantation in animal models, the grafts showed long-term patency, resistance to thrombosis, and progressive replacement of hiPSC-ECs by host endothelial cells, high-lighting their regenerative and integrative potential. The study emphasizes the pivotal role of hemodynamic conditioning and key regulators such as KLF2 in promoting endothelial quiescence and vascular homeostasis. It further explores alternative strategies like endothelial colony-forming cells (ECFCs) and microfluidic systems for flow-induced maturation. Clinically, this approach offers a promising, scalable avenue for patient-specific, immune-compatible vascular grafts applicable in congenital heart disease, dialysis access, vascular grafts and coronary bypass. While challenges such as long-term durability and mechanical reinforcement remain, this research marks a transformative step toward functional, off-the-shelf vascular grafts. Park et al.'s work bridges biomimicry with regenerative medicine, paving the way for next-generation vascular therapies rooted in endothelial mechanobiology and personalized bioengineering.

**Keywords** Tissue engineering · Vascular conduits · hiPSC-ECs · TEVCs · dHUAs · Decellularized human umbilical arteries · Shear stress · Bioreactor training

<figure><img src="image_2.png" /></figure>

## Introduction

In the rapidly evolving landscape of transitioning from reconstructive to regenerative medicine, the quest for vascular grafts that seamlessly integrate with host tissues and mimic the properties of native vasculature remains a major focus [1]. Vascular tissue is subject to a wide range of biomechanical constraints [2], and achieving long-term graft patency remains a formidable challenge. Infection and thrombosis, in particular, remain critical hurdles to overcome, especially with synthetic biomaterials [3, 4]. Moreover, the lack of growth potential in commonly available prostheses and grafts significantly limits reconstructive options in the pediatric population, where the need for adaptable and durable vascular substitutes is critical [5]. The latest article from Park et al., recently published in *Cell*

<footnote>David M. Smadja
david.smadja@me.com</footnote>

<footnote n="1">¹ Service de chirurgie plastique, reconstructrice et esthétique, Hospices Civils de Lyon, Lyon, France</footnote>

<footnote n="2">² Suivi immunologique des thérapeutiques innovantes, UMR1236, Inserm, EFS, Université de Rennes, Rennes, France</footnote>

<footnote n="3">³ Service de chirurgie plastique, reconstructrice et esthétique, CHU de Rennes, Université de Rennes, Rennes, France</footnote>

<footnote n="4">⁴ Cedars-Sinai Medical Center, Los Angeles, CA, USA</footnote>

<footnote n="5">⁵ Paris Cité University, INSERM UMR-S 970, Paris Cardiovascular Research Centre, Paris, France</footnote>

<footnote n="6">⁶ Hematology Department, Assistance Publique Hôpitaux de Paris-Centre Université de Paris (APHP-CUP), European Hospital Georges Pompidou, 56 rue Leblanc, Paris 75015, France</footnote>
*Stem Cell* [6], presents an elegant and paradigm-shifting approach to the development of fully biologic endothelialized tissue-engineered vascular conduits (TEVCs), offering a promising path forward in vascular surgery but also in the treatment of congenital heart disease. Their work harnesses the power of human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs), leveraging shear stress training in flow bioreactors to enhance endothelial function. This strategy not only prevented thrombosis upon implantation but also promoted long-term vascular integration by enabling the gradual replacement of hiPSC-ECs with host-derived endothelial cells. The implications of these findings extend far beyond the laboratory, offering a clinically translatable solution for patients with vascular diseases.

Through this concise, comprehensive review, we wish to leverage their findings and discuss the current challenges and future perspectives of vascular tissue engineering.

## A Breakthrough in Vascular Tissue Engineering

Historically, vascular grafts have suffered from limitations such as thrombotic complications, immune rejection, and lack of growth potential, particularly when synthetic materials are used [7, 8]. Alternatively, previous attempts to engineer vascular conduits have utilized polymeric scaffolds seeded with autologous bone marrow cells. However, these strategies frequently resulted in graft stenosis, largely driven by inflammatory responses. Multiple challenges remain, including selecting materials with optimal porosity, mitigating inflammation, and ensuring long-term graft patency. Moreover, the need for highly tailored bioengineering solutions, coupled with their substantial expense and technical demands, continues to hinder broad clinical adoption. Moreover, the hemocompatibility of biomaterials -even those that are not inherently vascular but remain in direct contact with blood- has been a focus of research in recent years [9–11] with growing efforts aimed at transitioning from “bio-tolerated” materials to real biocompatibility [12]. In the same idea, Cohen et al. described a novel method for creating vascular chimerism by partially decellularizing donor organs, specifically removing only the vascular endothelium while preserving the rest of the tissue [13]. This partial decellularization reflects a deliberate balance between reducing immunogenicity and avoiding excessive matrix destruction, which can compromise organ function. By targeting only the vascular lining, the structural and biochemical integrity of the organ is largely maintained. Human placental endothelial progenitor cells (EPCs) were then used to repopulate the vasculature, effectively humanizing the graft’s inner lining [13]. The result is a chimeric

organ with improved immune compatibility, a promising step for safer organ transplantation.

To address these constraints, the ultimate solution would be to develop off-the-shelf, pre-endothelialized universal scaffolds capable of promoting integration and maintaining long-term function. Another approach relies on post-implantation endothelialization of the construct, which, to date, represents one of the most promising strategies for achieving in vivo integration. As a relevant application, the safety of total artificial heart (TAH) implants, especially regarding thrombosis, has been associated with their potential for membrane re-endothelialization [14], with pericardial membranes playing a pivotal role. The concept of TAH has existed for over 50 years, originally developed as a temporary life-saving measure for patients with biventricular heart failure, primarily serving as a bridge to heart transplantation. A new generation of artificial hearts has emerged, including the Aeson TAH (A-TAH) developed by Carmat (Velizy-Villacoublay, France). The first human implantation of this device took place in 2013 in France [15], and more than 100 patients have been implanted so far. Unlike its predecessors, the A-TAH is designed to minimize hemolysis and prevent acquired von Willebrand syndrome, offering a more biocompatible solution [16]. It has been validated as a bridge to transplantation while requiring only minimal anticoagulation therapy [17]. Its unique design incorporates hemocompatible materials, with all blood-contacting surfaces covered by membranes derived from bovine pericardium, an engineered xenogeneic tissue widely used in bioprosthetic valves for over three decades [18]. The use of glutaraldehyde-fixed xenogeneic tissue in the A-TAH significantly reduces immunogenicity, making it the most advanced bioprosthetic artificial heart to date. Recent studies have suggested that this tissue may serve as a scaffold for neo-endothelialization, promoting the formation of a non-thrombogenic surface [19]. Emerging evidence indicates that endothelial cells responsible for this process originate from circulating blood [20], further supporting the notion that an optimal total artificial heart could integrate elements of both xenotransplantation and cutting-edge biomedical engineering.

These findings provide crucial clinical and physiological validation of the need to reendothelialize materials in direct contact with blood, reinforcing the paradigm shift in vascular biomaterial design. In this context, the groundbreaking study by Park et al. represents a revolutionary departure from traditional approaches, leveraging decellularized human umbilical arteries (dHUAs) as biological scaffolds [6]. By closely replicating the native extracellular matrix (ECM) of blood vessels, this approach paves the way for a new era in vascular engineering, bridging biomimicry and regenerative medicine to achieve superior hemocompatibility and
long-term functionality. Their methodology involves coating the luminal surface of dHUAs with hiPSC-ECs under precisely controlled shear stress conditions in bioreactors, a process that induces endothelial maturation and antithrombotic functionality. This training is critical, as it mimics the physiological hemodynamic forces experienced by endothelial cells in vivo, thereby enhancing their resistance to thrombosis and optimizing their functional longevity. Upon implantation into the inferior vena cava (IVC) of nude rats, these endothelialized TEVCs remained patent, resisted thrombus formation, and were progressively repopulated by host endothelial cells, a critical hallmark of successful vascular graft integration.

## Shear Stress Training: A Game-Changer in Endothelial Function

Shear stress, the tangential force exerted by blood flow on the endothelium, is increasingly recognized as a critical regulator of vascular homeostasis, endothelial phenotype, and tissue-engineered graft performance. In physiological conditions, steady laminar shear stress (LSS), typically observed in straight arterial regions, plays a protective role by promoting endothelial quiescence, nitric oxide (NO) production, and anti-inflammatory gene expression. In contrast, the disturbed flow patterns found at vascular curves, branch points, and bifurcations, known as oscillatory shear stress, promote endothelial dysfunction by triggering inflammatory responses and activating gene expression profiles associated with atherosclerosis susceptibility (Fig. 1). The

mechanotransduction of shear stress is mediated through a complex network of mechanosensors and signaling cascades that ultimately converge on cytoprotective gene expression and endothelial alignment along the flow vector. Furthermore, recent insights into metabolo-epigenetics have revealed that shear stress not only affects transcriptomic profiles but also reshapes the epigenetic and metabolic landscape of endothelial cells, suggesting durable reprogramming effects that extend beyond the immediate mechanical stimulus [21, 22]. Shear stress training emerges bioengineering tool that conditions stem cell-derived endothelial cells into a therapeutically competent state to promote endothelial quiescence and stability, reduce early thrombosis, and mitigate inflammation [23, 24].

One of the most compelling aspects of the Park's study is the role of shear stress conditioning in the maturation of hiPSC-ECs. However, translating these principles into functional TEVCs has remained an ongoing challenge, which Park et al. addressed by implementing a gradual shear stress training regimen. The exposure of hiPSC-ECs to an initial arterial-like shear stress of 15 dynes/cm², followed by a ramp-down to 5 dynes/cm², enabled simulating the hemodynamic environment of the IVC. This process induced robust expression of endothelial nitric oxide synthase (eNOS), tissue factor pathway inhibitor (TFPI), and tissue plasminogen activator (tPA), key markers of an antithrombotic endothelial phenotype. In contrast, TEVCs seeded with static (non-trained) hiPSC-ECs exhibited higher fibrinogen adsorption, reduced endothelial coverage, and increased thrombus formation upon implantation. The importance of this finding cannot be overstated. It highlights the necessity of shear

<figure><img src="image_3.png" /><figcaption>**Fig. 1** The impact of shear stress on endothelial cells and its utilization for biosubstrate preconditioning</figcaption></figure>
training in generating physiologically competent endothelial
cells capable of maintaining vessel patency. This principle
could be extended beyond vascular grafts to bioengineered
organ vasculature, endothelialized stents, and even syn-
thetic microvasculature for organ-on-chip models. Recent
advancements in vascular tissue engineering have empha-
sized the critical role of endothelialization in improving graft
function and longevity. Among these innovations, the study
by Park et al. has demonstrated how endothelial shear stress
conditioning enhances vascular graft performance by opti-
mizing the functionality of hiPSC-ECs. Blood flow-induced
shear stress plays a pivotal role in regulating endothelial
cell function and vascular structure. The transcription factor
KLF2 has been identified as a key mediator of this response,
promoting an anti-inflammatory and quiescent endothelial
phenotype under laminar flow conditions [25–29]. While
its effects have been extensively studied in two-dimen-
sional models, its application in three-dimensional engi-
neered vasculature remains underexplored. To address this
gap, researchers have developed microvascular networks
(MVNs) incorporating KLF2-based endothelial cell flow
sensors within microfluidic systems, applying continuous
flow to mimic physiological conditions [25]. This approach
has yielded significant findings, including increased vessel
diameter, reduced vascular resistance, and enhanced bar-
rier function, all of which contribute to reduced platelet
adhesion and improved hemocompatibility. These results
underscore the potential of KLF2-based flow training as a
transformative method for optimizing bioengineered vas-
cular grafts. The role of shear stress is further emphasized
in vascular dysfunction in organ transplantation, highlight-
ing the detrimental effects of the absence of intravascular
flow on endothelial function [30]. Temporary flow cessa-
tion, such as observed during cold organ storage, leads to
acute endothelial dysfunction and apoptosis due to the rapid
loss of KLF2 expression and its downstream vasoprotective
targets. This endothelial impairment is a key contributor to
post-transplant graft failure through the noxious endothelial
ischemia-reperfusion injury (IRI) cascade [31, 32]. Recent
work has shown that supplementing preservation solu-
tions with pharmacological agents, such as simvastatin, can
restore KLF2 expression, maintaining endothelial integrity
and preventing apoptosis [26, 27, 30]. These findings under-
score the essential role of flow in sustaining endothelial
homeostasis and reinforce the necessity of shear stress con-
ditioning in bioengineered vascular grafts to enhance their
longevity and function. Advancements in vascular tissue
engineering have further explored KLF2-mediated endothe-
lial conditioning through microfluidic-based systems. Such
an approach involves engineered microvascular networks
(MVNs) incorporating KLF2-based endothelial cell flow
sensors within microfluidic devices, where continuous flow

application mimics physiological conditions. This innova-
tive system has demonstrated significant benefits, including
increased vessel diameter, reduced vascular resistance, and
improved endothelial barrier function, ultimately reducing
platelet adhesion and thrombotic risks. These results con-
firm that shear stress is a biomechanical force and a critical
determinant of endothelial health [33].

Endothelial Replacement and Host
Integration

For long-term maintenance of vascular permeability and
growth potential, bioconstructs must achieve effective
biointegration with the host. Fibrotic tissue has long been
investigated as a potential source for autologous grafting, but
despite initial biocompatibility, long-term outcomes remain
[34, 35]. Notably, vessels possess their own microvascular
and lymphatic networks, collectively known as the *vasa vasorum* [36]. These structures play an integral role in vascular
physiology and repair mechanisms, as seen in conditions such
as coronary artery disease and cardiac allograft vasculopathy
[37], repair, such as in the case of coronary disease, and
cardiac transplant arteriopathy [38]. These examples highlight
the critical importance of enabling inosculation [39] and
neovascularization of implanted constructs to ensure optimal
biointegration [40]. This process may also be essential for
facilitating re-endothelialization of the grafted vessel, a key
element in ensuring both its short- and long-term function and
viability. The principle of integration, both endothelial and
transmural, is fundamental to the success of tissue-engineered
vascular constructs. As such, the selection of scaffold material
becomes a critical determinant of performance. This concept
has been central to the field of tissue engineering since its
inception over four decades ago. Synthetic scaffolds offer
reliable mechanical strength and structural integrity, yet they
often fall short in providing the biological cues necessary for
host cell recruitment and integration. In contrast, biologically
derived scaffolds, though more fragile mechanically, tend to
promote superior biointegration and immunocompatibility.
Hydrogels, too, have demonstrated potential by supporting
cell viability and promoting matrix remodeling; however,
they are often limited by their lack of mechanical robustness
and cellular integration [41–43]. Emerging hybrid strategies
seek to bridge this divide by combining synthetic materials
with the biological complexity of natural extracellular
matrices [44, 45]. Specifically, biologic scaffolds derived
from donor tissues of either the same or different species,
once decellularized, are emerging as valuable platforms.
They retain natural structural features and biochemical cues,
supporting both cell repopulation and the regeneration of
vascular tissue [46].
Park et al. showed that the hiPSC-ECs were progressively replaced by host-derived endothelial cells within a matter of weeks post-implantation. By day 7, the majority of hiPSC-ECs had been replaced, yet key antithrombotic markers such as TFPI, tPA, and glycocalyx components remained intact, suggesting that host ECs had seamlessly assumed endothelial function. This phenomenon underscores the bio-compatibility and regenerative potential of these TEVCs, as host cells integrate into the graft and contribute to long-term endothelial maintenance. Unlike synthetic grafts that may induce chronic inflammation or immune rejection, the use of biological scaffolds coupled with transient hiPSC-EC coating allows for a more natural transition to host-derived endothelium.

## Immunomodulatory Properties of Engineered Stem cell-derived Endothelial Cells

Recent advances in vascular tissue engineering have emphasized the central role of endothelial immunobiology in the development of functional and durable immune-compatible vascular grafts [47, 48]. ECs are immunologically active sentinels that orchestrate local and systemic immune responses [49]. Under homeostatic conditions, quiescent ECs maintain vascular integrity and immune tolerance by expressing low levels of major histocompatibility complex (MHC) class I molecules and negligible levels of MHC class II or costimulatory molecules such as CD80 and CD86 [50]. They also secrete anti-inflammatory mediators such as transforming growth factor-beta (TGF-β) [51, 52] and nitric oxide (NO) [53], which preserves the endothelium balance [54]. However, under inflammatory or mechanical stress, ECs undergo phenotypic switching with an upregulation of MHC class II [55, 56], adhesion molecule ICAM-1 [57], and proinflammatory cytokines such as IL-6 and IL-1β [58, 59] thus which promotes the recruitment of monocytes and neutrophils and triggers the activation of CD4⁺ T cells [57].

This immunologic plasticity is particularly relevant in the context of engineered grafts, where ECs can influence both innate and adaptive immune responses at the blood-graft interface. Park et al. harnessed this immunoregulatory potential by exposing hiPSC-ECs to physiological shear stress in a flow bioreactor, inducing a quiescent, anti-inflammatory phenotype. These vascular constructs showed increased expression of antithrombotic markers (eNOS, KLF2, KLF4) and reduced levels of thrombogenic markers (E-selectin, P-selectin, ICAM-1, VCAM-1) compared to statically cultured EC-coated grafts [6]. Shear stress-responsive transcription factors such as Krüppel-like factor 2 (KLF2) and KLF4 are central to this process, repressing

NF-κB signaling [60] and increasing endothelial nitric-oxide synthase expression [61] which promotes vascular homeostasis [62]. Importantly, Park et al. also observed gradual replacement of the implanted hiPSC-ECs by host-derived ECs, suggesting a process of immune-mediated remodeling and integration, rather than immune rejection. This phenomenon highlights the possibilities for the temporary use of engineered ECs as immunomodulatory scaffolds, priming the local environment for host repopulation. However, the immunogenicity of hiPSC-derived cells remains a significant challenge. Although hiPSC-ECs are generally considered immune-compatible when derived from autologous sources [63], studies have shown variable expression of danger-associated molecular patterns (DAMPs) such as High mobility group box 1 (HMGB1) [64, 65] and HLA molecules, particularly when cells are incompletely differentiated or exposed to inflammatory stimuli [66]. Consequently, allogeneic hiPSC-ECs used in off-the-shelf constructs must be carefully evaluated for their potential to activate host T cells or NK cells. Significant advances have been recently made to overcome the immunogenicity of allogeneic cell therapies, including strategies such as HLA matching, gene editing, and immunosuppressive coatings. Remarkably, research by Schrepfer and colleagues showed that endothelial cells generated from mouse or human induced pluripotent stem cells (iPSCs), modified to lack MHC class I and II expression and to overexpress CD47, were able to persist long-term in allogeneic hosts with complete MHC mismatch. These engineered cells avoided immune system attack without requiring immunosuppressive therapy and maintained their ability to fulfill complete differentiation [67]. Overall, these findings highlight the importance of integrating immunological considerations into vascular graft design to develop universally compatible and long-lasting regenerative vascular therapies.

## Clinical Implications: From Bench To Bedside

Cryopreserved arterial allografts harvested from human cadavers exhibit low immunogenicity due to cellular depletion during processing [68]. They are primarily used in vascular surgery when autologous grafts are unavailable, especially for infected prosthetic graft replacements or critical limb ischemia [69]. Despite their reduced antigenicity, chronic immune-mediated degradation may occur over time [70]. Allografts offer better resistance to infection compared to synthetic prostheses [71]. However, their long-term durability remains a clinical challenge [72]. Beyond congenital heart disease, endothelialized biomaterials hold significant potential for applications in peripheral artery disease, arteriovenous fistula creation for dialysis patients,
and coronary artery bypass grafting (CABG). This mecha-
nistic gap is also critical in tissue engineered approaches in
reconstructive surgery [73]. The role of endothelialized con-
structs in personalized medicine is promising particularly
for endothelial derived cells [74, 75], as patient-derived
hiPSC-ECs could be used to generate immune-compatible,
patient-specific vascular grafts and vascularized engineered
constructs. In addition to hiPSC-ECs, endothelial colony-
forming cells (ECFCs) emerge as a compelling alternative
for this approach [48, 76–78]. ECFCs represent a promising
source of endothelial cells due to their strong proliferative
and vasculogenic potential as well as host integration and
hemocompatibility properties. Unlike hiPSC-ECs, which
require differentiation protocols and extensive bioreactor
conditioning, ECFCs are naturally primed for vascular inte-
gration and have demonstrated high regenerative proper-
ties in preclinical models, particularly contrasting to cells
embryonic stem cells or adult blood-derived cells [79].
Integrating ECFCs with shear stress-based endothelial con-
ditioning, such as KLF2 activation [80, 81], could further
enhance the stability, functionality, and long-term patency
of engineered vascular grafts. This dual approach, leverag-
ing the biomechanical influence of shear stress alongside
the inherent vasculogenic properties of ECFCs, could pave
the way for next-generation bioengineered vessels, offering
improved hemocompatibility and enhanced graft integra-
tion in clinical applications (Fig. 2).

While Park's study represents a major advance in vascu-
lar tissue engineering, several key challenges remain:

1. **Long-Term Functionality:** While short-term patency was demonstrated, extended studies are needed to evaluate TEVC durability over several months to years. However, results obtained from small-caliber vessels in rodent models cannot be directly extrapolated to clinical settings. The porcine model is considered superior, offering more relevant anatomical and physiological similarities to human vasculature for translational evaluation.

2. **Mechanical Strength** - Although dHUAs provide a natural ECM scaffold, further reinforcement may be required to withstand higher-pressure arterial environments.

3. **Clinical Translation** - Standardization of hiPSC-EC differentiation protocols and scalable bioreactor systems will be crucial for moving this technology from preclinical models to human trials. Combination with in vivo preconditioning approaches could improve bio-compatibility and full vascular integration [82].

4. **Host-related limitations** - While scaffold properties, endothelialization, and hemodynamic factors are critical for long-term patency, clinical outcomes are also heavily influenced by patient- and vessel-related factors. The burden of cardiovascular risk factors, such as smoking, chronic low-grade inflammation, dyslipidemia, and diabetes, remains among the strongest determinants of long-term graft performance [83]. Moreover, health disparities and the high prevalence of cardiovascular disease may partly reflect genetic differences in endothelial

<figure><img src="image_4.png" /><figcaption>**Fig. 2** Clinical relevance and perspectives for endothelialized vascular bioconstructs</figcaption></figure>
shear stress responses, potentially influencing endothelialization and vascular integration. Indeed, Wei et al. demonstrated that ECFCs from African American and Caucasian American donors exhibit significant differences in gene expression, particularly within shear stress—responsive pathways—a key regulator of endothelial phenotype, vascular tone, and homeostasis [81]. These genetically influenced variations suggest that host-related factors, including ancestral genomic background, can modulate endothelial cell behavior under hemodynamic forces, potentially affecting processes such as endothelialization, vascular repair, and integration of grafts or devices. Hemodynamic conditions, particularly shear stress, are essential considerations; as observed with free grafts in CABG, conduits originating from low-pressure circulations may be especially vulnerable when exposed to high systemic arterial pressures [84, 85]. Additionally, the quality of the peripheral outflow could have a profound impact on durability. Arterial grafts anastomosed to diffusely diseased recipient arteries, common in advanced diabetes, coronary artery disease, or peripheral arterial disease, show significantly reduced longevity [86]. These limitations are not unique to decellularized scaffolds and must be acknowledged when evaluating any allogeneic vascular graft.

Additionally, the study raises intriguing questions about the mechanisms driving host endothelial cell recruitment. Future research should explore whether specific cytokine signals or extracellular vesicles mediate the transition from hiPSC-ECs to host-derived endothelium. Understanding these pathways could unlock new strategies for enhancing vascular graft integration. The concepts of bioengineering have progressively evolved, from initially attempting to mimic isolated biological properties to now encompassing the full spectrum of graft maturation, both ex vivo and in vivo, with an emphasis on early biocompatibility and long-term functionality.

All in all, Park et al. have provided a compelling blueprint for the next generation of vascular grafts, one that seamlessly integrates stem cell technology, endothelial biomechanics, and regenerative medicine. Their approach addresses many of the historical challenges associated with vascular tissue engineering, offering a clinically relevant, thrombosis-resistant, and host-integrating solution. As we stand at the intersection of bioengineering and translational medicine, studies like this push the boundaries of what is possible in cardiovascular surgery and vascular replacement therapies. With continued innovation, endothelialized biomaterials may soon become a mainstay in treating vascular diseases, paving the way for a new era of personalized,

regenerative medicine. The journey from bench to bedside is never straightforward, but with such advancements, the future of vascular surgery looks undeniably promising.

**Author Contributions** Yanis Berkane: Writing — original draft; Writing — review and editing; Literature analysis.Haizam Oubari: Writing — review and editing; Investigation; Literature analysis.Maxime Jeljeli: Writing — review and editing; Methodology support; Validation.Alexandre G. Lellouch: Writing — review and editing; Resources; Project administration.David M. Smadja: Conceptualization; Writing — original draft; Supervision; Funding acquisition, Project administration.All authors have read and approved the final version of the manuscript.

**Funding** Open access funding provided by SCELC, Statewide California Electronic Library Consortium. Our work is supported by the Priority Research Program and Equipment (PEPR) "Biotherapies and Bioproduction of Innovative Therapies" (BBTI), as a part of the government's "France 2030" investment plan, through the program "Bioengineered Skin-France" (ANR-22-PEBI-0010).

**Data Availability** No datasets were generated or analysed during the current study.

## Declarations

**Ethical Approval** This study so not involve human participants and were not reviewed by any ethical committee.

**Consent to Participate** Not applicable.

**Consent to Publish** Not applicable.

**Competing interests** The authors declare no competing interests.

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