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Barachini, S.; Ghelardoni, S.; Madonna, R. Vascular Progenitor Cells. Encyclopedia. Available online: (accessed on 14 June 2024).
Barachini S, Ghelardoni S, Madonna R. Vascular Progenitor Cells. Encyclopedia. Available at: Accessed June 14, 2024.
Barachini, Serena, Sandra Ghelardoni, Rosalinda Madonna. "Vascular Progenitor Cells" Encyclopedia, (accessed June 14, 2024).
Barachini, S., Ghelardoni, S., & Madonna, R. (2023, April 06). Vascular Progenitor Cells. In Encyclopedia.
Barachini, Serena, et al. "Vascular Progenitor Cells." Encyclopedia. Web. 06 April, 2023.
Vascular Progenitor Cells

Vascular progenitor cells are activated to repair and form a neointima following vascular damage such as hypertension, atherosclerosis, diabetes, trauma, hypoxia, primary cancerous lesions and metastases as well as catheter interventions. They play a key role not only in the resolution of the vascular lesion but also in the adult neovascularization and angiogenesis sprouting (i.e., the growth of new capillaries from pre-existing ones), often associated with carcinogenesis, favoring the formation of metastases, survival and progression of tumors.

vascular progenitor cells angiogenesis cancer metastasis

1. Introduction

To date, in addition to circulating progenitors, different types of resident vascular stem/progenitor cells (VSCs) have been characterized and their role in vascular repair and the development of the disease has been evaluated. VSCs are defined as “cells that reside within the blood vessel wall and can differentiate into all of the cell types that make up a functional blood vessel” [1]. In particular, VSCs can differentiate into endothelial cells (ECs), pericytes in capillaries, smooth muscle and adventitia cells in larger vessels. Adult VSCs, quiescent in their niches, can be mobilized in response to injury or inflammation, to form new vessels during vascular repair. Several processes underlie vascular repair, and angiogenesis is the best known process. Angiogenesis is characterized by the sprouting of new capillaries from postcapillary venules [2] by in situ proliferation and the migration of pre-existing ECs. During embryonic development, the de novo formation of the blood vessel is defined as vasculogenesis, while in the adult it is postnatal vasculogenesis [3]. Moreover, arteriogenesis is the maturation and formation of larger diameter arteries from pre-existing capillaries or collateral arteries [4]. Finally, neovascularization includes all processes: angiogenesis, arteriogenesis and vasculogenesis [5].
Several studies have demonstrated that different subtypes of VSCs isolated from different tissues, such as EPCs, SMPCs and mesangiogenic progenitor cells (MPCs), can differentiate into various vascular cells to form the vascular wall in the course of vascular repair [6][7]. Three distinct layers form the vascular wall of arteries and veins: tunica intima, a single layer of ECs; tunica media composed of smooth muscle and elastic fibers; and tunica adventitia. In recent years, studies have shown that not only could the adventitia represent a complex depot for VSCs involved in endothelium repair [8], but also the intima is composed of VSCs that have an important role in the onset and progression of vascular remodeling diseases. VSCs could be the in situ equivalent of bone marrow (BM), MSCs or as perivascular stromal cells due to their perivascular location and multilineage potential [9]. Thus, the finding of VSCs suggests the presence of a vessel wall niche in which multipotent resident progenitor cells are capable under appropriate stimuli of regenerating small and large vessels [10].
In addition, VSCs also play a role in the angiogenesis involved in tumors. Several distinct biological processes, orchestrated by a series of secreted factors and signaling pathways also involving non-endothelial cells, progenitors or tumor stem cells, give rise to tumor vascularization [11].

2. Endothelial Progenitor Cells

Since their first identification in 1997 [12], EPCs have been extensively studied for their potential as endothelial lineage progenitors, having the ability to proliferate and differentiate into mature ECs in vitro, and to generate new vessels in vivo [13]. There are several studies regarding the biology of EPCs, the origin of surface markers and the hierarchy of differentiation, but there have been considerable controversies, especially in the different isolation method used and in the EPC origin.
The adult hematopoietic system is a very heterogeneous and dynamic process. The existence of the hemangioblast, capable of differentiating into endothelial and hematopoietic cells, was shown two decades ago by Asahara and colleagues, who successfully isolated EPCs from human peripheral blood [14][15]. Since then, further studies support not only the existence of EPCs and their role in the formation of a new vessel [10], but the existence of a hemogenic endothelium (HE). HE has a hemogenic capacity and displays an Flk1+ (fetal liver Kinase 1) c-Kit+CD45−side population phenotype representing a heterogenous source of various types of progenitor cells generated not only during embryogenesis, but also in the BM of late fetus/young adults [10].
The heterogeneity of HE suggests that HE cells are already “primed” to become specific types of stem or progenitor cells when still undergoing the endothelial-to-hematopoietic transition (EHT), a process involving the transcription factor Runx1. HE cells undergo an EHT giving rise to hematopoietic stem cells (HSCs) with intermediate stages, such as pre-HE, revealed by scRNA-seq studies showing the differentiation trajectory of EHT [16][17]. Subsequently, hemogenic angioblasts are thought to migrate within the fetal liver and fetal BM as these tissues develop. Recently, Zhao et al. [18], using photoconvertible labeling, time-lapse imaging and a single-cell RNA-sequencing analysis in a zebrafish model, found that HE and ECs arise from a common flk1+ precursor, which they refer to as hemogenic angioblasts, and their distinct fate is regulated by ETS transcription factors Etv2. Interestingly, Etv2 has been found to be involved in tumor angiogenesis [19].
EPCs were originally shown as circulating cells that have the potential to differentiate into mature ECs, being involved in postnatal vasculogenesis. Most of the scientific studies, regarding the biology of EPCs, used CD34+ or CD133+ cells in human peripheral blood mononuclear cells and found their commitment into the endothelial lineage cell in vitro and their integration into EC in the formation of a new blood vessel in vivo [20], supporting the evidence that cells derived from CD34+ are incorporated into the human vasculature. However, EPCs have been shown to be actually a mixture of several cell types, such as early and late EPC, explaining some contrasting results due to the inconsistency of culture condition standardization [21][22].
EPCs have been isolated from different sources: bone marrow, spleen, umbilical cord blood, adipose tissue, placenta. Ingram et al. [23] revealed intima-derived EPCs expressing CD31, von Willebrand factor (vWF), CD146, Flk-1, CD144 and CD105, suggesting a hierarchical organization of different EPC subpopulations. Subsequent data of Bearzi et al. [24] demonstrated that all three mural layers of human coronary arteries include small groups of clonogenic VSCs, expressing c-kit+ VEGFR2+ and CD45+ that are able to differentiate between ECs and SMCs.
The early theory about the use of circulating EPCs for vascular repair has been challenged by later studies indicating that CD34+ cells derived from BM were more likely to differentiate into inflammatory cells and not EPCs. Instead, high-proliferative and pro-angiogenic EPCs within the vessel wall have been found to have a similar clonogenic capacity to repair endothelium. Further research has suggested that CD34+ cells may be a tissue-resident source for EPCs. EPCs are promising for cardiovascular therapy, but clinical research on EPC-captured stents has shown limited efficacy. However, CD34+ cell transplantation in myocardial tissue has been shown to be safe and efficient in patients with heart disease [22].
Recently, embryonic-like stem cells (VSELs) [25] have been identified as very small cells (5–7 μm) with large euchromatin-containing nuclei and cytoplasm enriched in mitochondria expressing pluripotent octamer-binding transcription factor 4 (OCT-4) [26]. VSELs have been proposed to originate from germline-related cells and play a role as a backup population for tissue-committed monopotent stem cells. VSELs are deposited in developing organs during embryogenesis as highly quiescent cells but are mobilized into circulation during stress stimuli. It has been speculated that VSELs are at the top of the stem cell hierarchy in BM, lacking the CD45 marker on their surface, and give rise to HSCs, EPCs and MSCs. VSEL specification in HSCs and EPCs may involve a presumed hemangioblast as an intermediate cell.
EPC has been shown as a therapeutic option to improve tissue function by enhancing angiogenesis, as well as neurogenesis in ischemic stroke and brain damage models [22]. In addition, EPC and MSC implanted together contribute to vessel formation in the ischemic muscle more effectively than EPC alone [27][28].
Until now, results are often conflicting, do not cover all the possible functions and applications of EPCs due to different isolation protocols and lack both a precise surface marker and a functional assay. At present, there is a need for a new classification of EPC according to their origin, phenotype and function, while also redefining EPCs with state-of-the-art multiomics technology.

3. Smooth Muscle Progenitor Cells

In new vessels, smooth muscle cells stabilize mechanically the vascular wall and help in regulating vascular tone and blood flow. A long-held view was that SMCs consist of heterogeneous populations with remarkable plasticity, and exhibit either a proliferative and migratory phenotype with the presence of stem cell markers, or a quiescent, contractile and mature phenotype [29].
There are different views regarding the origin of SMCs. Some suggest that they are heterogeneous, while others propose that they originate from multipotent vascular stem cells and differentiate into specific subpopulations with distinct functions. Early studies in mice indicated a predominant role for BM as a potential source of vascular progenitors [30]. Subsequent studies, however, failed to reproduce these data [31]. Other reports have identified vascular SMPCs in microvascular pericyte, adventitial MSC and vascular ECs, suitable for the endothelial-to-mesenchymal transformation (EndMT) [10]. Furthermore, recent data showed JAG1-induced Notch signaling is critical for the regulation of EPC differentiation and proliferation and promotes MSC differentiation into SMCs [32].
Recent investigations showed the adventitia in the vessel as a complex layer of wall consisting of different types of cells, including resident progenitor cells, located in a specialized niche at the media–adventitia border. More than a decade ago [33], Sca1+ cells in the adventitial layer of the vessel wall were proposed as stem cells for SMCs although it was not proven to have the in vivo function in vascular injury and vessel remodeling, due to technical limitations at that time.
Later, Kramann et al. [34], based on a lineage tracing study, demonstrated that Gli1+ MSC-like cells are adventitial progenitor cells; CD34, Sca-1 and PDGFR-β (platelet-derived growth factor receptor β)-positive; collaborating to neointima production and to restore after an acute damage to the femoral artery. Adventitial progenitors express Sca1 and CD34 and show a multipotent phenotype suitable to differentiate in vivo into adult SMCs, contributing to both intimal and adventitial remodeling [35]. The pluripotency-associated transcription factor, Klf4, is required for the preservation of the adventitial Sca1 progenitor cell phenotype. However, the origin of adventitial Sca1 progenitor cells remains unclear. Recently, Tang et al. [36], using single-cell RNA sequencing and genetic cell lineage tracing, proved that adventitial Sca1+ VSCs help in the formation of SMPCs and play a crucial role in vessel repair, identifying a potential therapeutic target for the treatment of cardiovascular diseases.
The adventitia may be a compartment that provides an appropriate microenvironment for VSCs [37], where Sca1+ progenitor cells and other adventitial stem cell populations are a backup system operating in conditions of loss or insufficiency of SMCs. This is also the site for the restricted domain of sonic hedgehog (Shh) signaling, which may provide a pivotal contribution in preserving vascular SMC progenitor cells resident in the artery wall [38][39]. In addition, SMCs, pericytes and ECs may have a common progenitor, namely, Flk1-positive embryonic cells [40] where FLK1 maintains the Sca-1+ progenitor cell phenotype.
VSCs in the adventitia can migrate into the media and differentiate into vascular SMCs facilitated by the disruption of the elastic lamellae to support their migration. A few expanding cells were found to be the origin of oligoclonal SMCs in injury-induced neointimal lesions and atherosclerotic plaques, as demonstrated by a recent paper. These cells could either be progenitors of quiescent SMCs or have the ability to dedifferentiate into progenitors [41]. SMCs in lesions comprise all the stages of differentiation, thus exhibiting a variety of phenotypes [37]. The elucidation of molecular pathways driving the plasticity, heterogeneity and differentiation of SMPCs may lead to the finding of new and more peculiar targets for disease prevention and treatment.

4. Mesangiogenic Progenitor Cells

The perivascular localization of mesenchymal precursors may justify their presence in a wide range of tissues and organs and suggest an angiogenic potential. MSCs are pluripotent, self-renewing, spindle-shaped cells isolated from adult tissues such as BM, adipose tissue and dental pulp and from perinatal tissues such as umbilical cord blood, placenta, amniotic fluid and umbilical cord Wharton’s jelly [42][43][44][45]. The features of MSC from various organs are different in phenotypes, differentiative potential and result from the influence of a local environment.
MSC derived from adventitial reticular cells express CD271 and CD146 markers and are located in the subendothelial layer of the sinusoids [46]. Moreover, another different population expressing CD271 but not CD146, located in the endostal niche, is able to generate MSCs [47]. In addition, two intra-vessel wall compartments, the adventitia and subendothelium, have been suggested as possible sites for MSC progenitors. However, a defined characterization of MSC and standardized protocols for their isolation and expansion are still lacking. BM-derived MSCs can differentiate into ECs and SMCs in vitro via modulation of growth factors. Non-medullary progenitor cells with pro-angiogenic capacities have been reported as CD34-positive/CD31-negative cells, expressing pericyte/MSC markers together with Sox2 and located in human saphenous veins [48]. It is now increasingly recognized that MSCs typically do not engraft after transplantation and have limited capabilities to trans-differentiate in vivo, but they exhibit their therapeutic effect in a paracrine manner through the secretion of bioactive factors (such as microRNA, transfer RNA, long non-coding RNA, growth factors, proteins and lipids) collectively referred to as the secretome [49]. Moreover, there are conflicting data regarding their angiogenic potential due to the heterogeneity of the primary MSC cultures utilized to generate endothelial progenitors.
The researchers recently isolated a new population of progenitors of mesengenic lineage progenitor cells from human BM with angiogenic potential, named mesangiogenic progenitor cells (MPCs), which are tissue-specific [50][51][52]. The researchers hypothesized that the presence of the MPCs could be responsible for conflicting data regarding the angiogenic potential of MSC cultures. By replacing fetal bovine serum with pooled human AB serum [53] in the culture medium of human BM-mononuclear cells, the researchers obtained a Ki-67-negative, adherent cell population with long telomeres, condensed chromatin and podosomal structures [54]. MPCs are quiescent, fried egg-shaped cells, positive for Nestin, CD31 and CD105 but negative for the expression of CD73, CD90, CD166 and CD271 and other typical markers for a mesenchymal phenotype such as MSCA-1.
The angiogenic potential of MPC was demonstrated by the standard angiogenesis assay in which MPCs formed capillary-like structures after multiple steps of differentiation [55]. Indeed, MPCs can begin sprouting when directly seeded in Matrigel 3D cultures, but they are unable to efficiently form tube-like structures without a differentiation step, suggesting that MPCs are a stem progenitor with angiogenic potential. MPCs have been shown to derive from a single-BM-cell population named Pop#8 [56]. This cell population has been sorted from adult human BM as CD45lowCD31brightCD64brightCD14neg and showed similarities to monocytoid progenitors. Gene expression data suggested the in vivo involvement of Pop#8 in maintaining the hematopoietic stem cell niche. Moreover, the high expression of CD31 and Nestin in MPCs suggests that these cells may represent a primitive progenitor for endothelial lineages. Nestin was originally reported as a 176 kDa class VI intermediate filament protein in neural stem cells of the embryonic and adult brain, and later in ECs [57]. The researchers also demonstrated that Nestin expression in benign human BM biopsies was detected in the ECs of small arteries and endosteal arterioles, and also in very small vessels, named NESTIN+ capillary-like tubes, suggesting Nestin is an associated marker of neovascularization [58].
A subset of progenitors with mesengenic potential has been isolated among BM-Nestin+ populations, as reported by Mendez-Ferrer et al. [59]. These cells express high levels of CXCL-12 and Ang-1, but they lack endothelial markers such as CD31, vascular endothelial cadherin or CD34 and limited data are available regarding their angiogenic potential [59]. In 2013, Kunisaki et al. [60] identified specialized perivascular populations using Nestin-GFP mice. They found that Nestin is highly expressed in quiescent cells near arterioles (NES-peri), while perivascular reticular cells closely related to sinusoids have a higher proliferation rate but a dim expression of Nestin (NES-retic).
Recently, by combining single-cell and spatially resolved transcriptomics [61], Cxcl12-Abundant-Reticular (CAR) cell subsets have been isolated in BM niches, i.e., Adipo-CARs localizing in the sinusoidal endothelium and Osteo-CARs localizing in the arteriolar endothelium. These cells behave as “professional cytokine-producing cells” and constitute perivascular micro-niches involved in the maintenance and differentiation of HSC.
Finally, MPCs are believed to be the ancestors of MSCs, and although their in situ localization has not been fully understood, it is probable that they reside in the tunica intima of BM vessels, in contact with CAR cells or the NES-peri population.

5. Pericytes

Pericytes coat microvascular capillaries, where they determine the formation, maturation, maintenance, stabilization and remodeling of the vascular system. They come into direct contact with underlying ECs, share some properties with MSCs and could trans-differentiate into myofibroblasts, SMCs and adipocytes, therefore modulating the vascular net and flow [62].
Classical markers that identify pericytes are CD13, CD146, α-SMA (smooth muscle α-actin), PDGFR-β, NG-2 (Neuron-glial antigen 2) and desmin, while other new markers are RGS5 (regulator of G protein signaling 5), DLK-1 (delta-like homolog 1) and Endosialin (CD248 or TEM1), but none of them can definitively define them due to their overlap with the other markers of other adjacent cells.
Pericytes play a pivotal role in both the vessel sprouting and stabilization phases of angiogenesis; the latter is initiated by the release of matrix metalloproteases from ECs and pericytes, allowing pericyte detachment and a transition from their quiescent phenotype to the actively proliferating one. Several angiogenic factors induce the migration of ECs and one single EC “tip cell” and recruit other ECs through the VEGF (vascular endothelial growth factor) gradient. The other ECs are called “stalk cells” and form the growing lumen. Vessel maturation is achieved via the secretion of TGF-β (transforming growth factor-β) and ANG1 (angiopoietin1) by ECs and pericytes [63].
The PDGF family has four members (A, B, C, D), and they activate two receptor tyrosine kinases (PDGFR-α and PDGFR-β) to induce downstream signaling pathways. PDGF-β dimer is a key regulator of vascular pericytes and is required for their recruitment to nascent blood vessels [32]. PDGF-C is also important in regulating VSCs and enhances their proliferation, migration and differentiation into ECs. PDGF receptors have been shown to have important effects on VSCs, and their overexpression increases the proliferation and migration of VSCs via ERK and PI3K/AKT activation. In addition to the mediating effects of PDGF, PDGF receptors can also mediate those of VEGF-A, promoting the migration and proliferation of MSCs via PDGFR-α and PDGFR-β [32].
The VEGF signaling pathway plays a critical role in vasculogenesis and angiogenesis, starting with the expression of VEGF receptors (VEGFRs) on primitive ECs. VEGF-A is the prototypical member of the VEGF family and is released in response to hypoxia or hypoperfusion of a tissue. VEGFR2 is the most important signaling receptor in vasculogenesis and angiogenesis, with high intracellular tyrosine kinase activity when activated. The knockout of VEGFR2 or VEGF-A results in early embryonic lethality due to the lack of organized vasculature [64]. Intracellularly, VEGFR2 activation propagates via a number of downstream signaling pathways, such as ERK signaling, inducing endothelial proliferation and differentiation and leading to the expression of cell adhesion molecules such as VE-cadherin. The control of the VEGFR expression is maintained by exogenous signaling such as the fibroblast growth factor (FGF) and TGF–β and negative feedback loops within the cell. Perivascular cells also express VEGF, primarily VEGF-A, which stabilizes newly formed vessels but does not promote endothelial cell migration. Pericytes have VEGFR1 on their cell surface, which sequesters VEGF from VEGFR2 on endothelial cells, preventing the initiation of angiogenesis in mature, quiescent vessels [64].
New investigations have reported that pericytes derive from human pluripotent stem cells, developing into MSCs and lastly differentiating into immature pericytes and SMCs. Immature pericytes can vary into type I and II pericytes, which propagate towards several tissues and organs where they carry out their functions [65].
Herrmann et al. [66] compared and characterized pericytes isolated from BM and adipose tissue as CD45-CD34-CD146+ cells. Their results showed that BM-derived cells demonstrated triadic differentiation potential, while adipocyte-derived cells had poor chondrogenic differentiation. This suggests that the microenvironment of the organ of origin may impact cell processes.
Recent studies using lineage tracing experiments have shown that the cell fate plasticity of endogenous pericytes in vivo is unclear. The transcription factor Tbx18 has been found to selectively mark pericytes and SMCs in multiple organs of adult mice [67], indicating that pericytes do not behave as tissue-resident multipotent progenitors. These findings highlight that the plasticity observed in vitro or following transplantation in vivo may be a consequence of the artificial cell culture environment.


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