On the origin and development of glioblastoma: multifaceted role of perivascular mesenchymal stromal cells
Acta Neuropathologica Communications volume 11, Article number: 104 (2023)
Glioblastoma, IDH wild-type is the most common and aggressive form of glial tumors. The exact mechanisms of glioblastoma oncogenesis, including the identification of the glioma-initiating cell, are yet to be discovered. Recent studies have led to the hypothesis that glioblastoma arises from neural stem cells and glial precursor cells and that cell lineage constitutes a key determinant of the glioblastoma molecular subtype. These findings brought significant advancement to the comprehension of gliomagenesis. However, the cellular origin of glioblastoma with mesenchymal molecular features remains elusive. Mesenchymal stromal cells emerge as potential glioblastoma-initiating cells, especially with regard to the mesenchymal molecular subtype. These fibroblast-like cells, which derive from the neural crest and reside in the perivascular niche, may underlie gliomagenesis and exert pro-tumoral effects within the tumor microenvironment. This review synthesizes the potential roles of mesenchymal stromal cells in the context of glioblastoma and provides novel research avenues to better understand this lethal disease.
Glioblastoma (GB), IDH wild-type (wt) is the most common and aggressive form of glial tumors, accounting for almost 50% of primary malignant central nervous system (CNS) tumors [1, 2]. It is classified as grade 4 in the World Health Organization (WHO) classification of tumors of the CNS. It belongs to the «adult-type diffuse glioma» family that also includes astrocytoma IDH-mutant (WHO grade 2, 3, or 4) and oligodendroglioma, IDH-mutant and 1p/19q-codeleted (WHO grade 2 or 3) .
As opposed to astrocytoma IDH-mutant WHO grade 4 (formerly, GB, IDH-mutant), GB, IDHwt arises de novo (without preexisting precursor lesion) and typically manifests rapidly after a short clinical history. Despite an aggressive multimodal therapeutic approach, GB IDHwt is associated with a dismal prognosis, showing a median survival of 8 months and an overall 5-year relative survival rate of 5.5% .
The exact mechanisms of glioblastoma oncogenesis are yet to be discovered. Over the last two decades, extensive and comprehensive molecular profiling of GB has brought new insights into gliomagenesis [3, 4]. The genomic and epigenomic landscape of GB have been thoroughly described, and biological subgroups have emerged, defining three molecular subtypes based on gene expression profiling signatures: proneural, classical, and mesenchymal [3, 5,6,7]. To date, it has not strongly impacted clinical practice, likely owing to marked intratumoral heterogeneity and differentiation plasticity of GB . However, it has provided new research avenues to understand better the GB pathogenesis, including the identification of the glioma-initiating cell.
Recent studies have led to the hypothesis that GB may arise from neural stem cells (NSC) and glial precursor cells, such as oligodendrocyte and astrocytic precursor cells [9, 10]. In addition, it has been shown that the originating cell lineage is crucial to tumor molecular stratification, independently of the driver mutation that it initially harbors [11, 12]. While glial or neuronal progenitor cells have been suggested to initiate proneural and classical GB, the cellular origin of mesenchymal glioblastoma remains elusive. Studies have described a potential proneural to mesenchymal transition (PMT) that may illustrate the transcriptomic plasticity of GB upon treatment or recurrence. Recently, neural crest (NC)-derived cells have emerged as potential cells of origin in mesenchymal GB . Herein, we discuss perivascular mesenchymal stromal cells (pMSC), also referred to as vascular fibroblasts (vFB), which originate from the NC, as potential candidates for the initiation of GB and their role in GB development .
GB, IDHwt is the most common malignant CNS tumor in adults. It accounts for approximately 15% of all intracranial neoplasms and almost 50% of all malignant CNS tumors. It preferentially affects older adults, with a peak incidence in patients aged 55–85 years (median age of 64 years). In the United States of America, GB, IDHwt is more common in males compared to females (M: F ratio of 1.58: 1) [1, 2]. To date, the only validated risk factor is ionizing radiation to the head and neck [15, 16]. On the contrary, decreased risk has been observed among individuals with a history of allergies or atopic diseases . Despite a multimodal therapeutic approach that includes surgery, radiotherapy, and chemotherapy, prognosis remains poor, with a 5-year survival rate of 5.5% [2, 17, 18].
Definition of GB
GB, IDHwt is a diffusely infiltrating high cellular glioma that characteristically shows microvascular proliferation and/or necrosis. As the former term « GB multiforme» suggests, GB morphology has remarkable inter-tumoral and intra-tumoral heterogeneity. Cellular pleomorphism includes small, undifferentiated, spindled, lipidized, granular, epithelioid, and/or giant cells. Secondary structures of Scherer illustrate the different routes that glioma cells can take to invade the brain: 1) the white matter tracts, 2) the vasculature (perivascular satellitosis), 3) the leptomeningeal space and 4) the brain parenchyma.
By definition, GB, IDHwt lacks mutations in IDH1 codon 132 and IDH2 codon 172. Molecularly, demonstration of TERT promoter mutations, EGFR gene amplification, and/or a gain of chromosome 7/ loss of chromosome 10 genotype is sufficient for the diagnosis of GB .
GB Molecular pathways
PI3K–AKT–mTOR and Ras/MAPK/ERK pathways
The PI3K and MAPK pathways, both activated by receptors tyrosine kinase (RTK), regulate many cellular processes, including cell proliferation. In approximately 90% of IDHwt GB, at least one activating alteration in the PI3K pathway is observed, including alterations of RTK genes, PI3K genes, and PTEN [3, 19]. Alterations of RTK genes are common in GB, involving EGFR (60%), PDGFRA (10–15%), MET (2–5%), or FGFR3 (~ 3%) [3, 5, 20]. PI3-kinase mutations are found in about 25% of GB . In addition, the NF1 gene, which encodes neurofibromin that functions as a negative regulator of RAS signaling, is deleted or mutated in 10% of cases .
The p53 pathway is altered in a large variety of cancer, including GB. Indeed, up to 90% of GB have an altered p53 signaling pathway, with mutation or deletion of TP53 in 20–25% of cases [3, 19]. In about 15% of GB, an amplification of MDM2 or MDM4 is observed, thus inhibiting p53 . Homozygous deletion of CDKN2A locus, which encodes the p14ARF protein that inhibits MDM2, is detected in about 60% of GB, resulting in an inactivation of the p53 pathway and the pRB pathway (see below) .
CDK4/6–CDKN2A/B–RB1 cell-cycle pathway
The pRB pathway represents a critical cell cycle checkpoint, suppressing cell cycle entry (Fig. 1). CDK4 and CDK6 suppress the downstream inhibition of pRB, allowing the progression from G1 to S phase of the cell cycle. P16, encoded by CDKN2A, inhibits CDK4 and CDK6. Up to 80% of GB show at least one alteration of the pRB pathway, including CDKN2A deletions, amplifications of CDK4/CDK6, and inactivating alterations of RB1 [3, 19].
GB molecular subtypes and the mesenchymal signature
Gene expression profiling has allowed the classification of GB into three distinct molecular subtypes: proneural, classical, and mesenchymal [3, 5,6,7]. Initially, this classification was based on the expression profile of 840 genes, but subsequent studies have shown that it can be simplified to rely on just 12 genes with good concordance (Table 1) . However, despite their correlation with distinct genetic aberrations and clinical characteristics, these molecular subtypes have not gained clear significance in clinical practice.
The proneural subtype is characterized by specific genetic alterations, including IDH1 mutation, TP53 mutation, PDGFRA amplification and/or mutation, and a glioma-CpG island methylator phenotype (G-CIMP) [5, 22]. Notably, both IDH1 mutations and G-CIMP are considered favorable prognostic factors. However, when excluding IDH-mutant tumors, the proneural subtype exhibits the worst prognosis among all subtypes .
The classical subtype is characterized by EGFR mutation/amplification and CDKN2A homozygous deletion.
Accounting for approximately 34% of GB, the mesenchymal subtype displays an expression profile characterized by mesenchymal markers, such as CHI3L1 and MET [5,6,7]. Mesenchymal subtype tumors are predominantly IDHwt and G-CIMP- and commonly harbor NF1 mutation [5, 22, 24]. In addition, they tend to correlate with poor response to radiation therapy and relatively poor outcome [7, 24]. The mesenchymal subtype is also characterized by high levels of angiogenic markers, such as CD31/PECAM-1, VEGF, flt1/VEGFR1, and kdr/VEGFR2 . Furthermore, it exhibits high expressions of immune-related genes, particularly proinflammatory genes and immunosuppressive genes [3, 5, 6, 25]. Several of these genes are involved in the recruitment of monocytes/macrophages (CSF-1, CCL2, CCL-22, TREM1, and TREM2) and in the macrophage-polarization towards an immunosuppressive M2-phenotype (CD163, CD204) . Notably, the mesenchymal subtype shows enrichment of macrophages and microglial cells, constituting the largest stroma cell population in GB [26,27,28].
The origin of GB
The exact cell of origin of GB has yet to be definitively identified. Several CNS cell types within the CNS, including neural precursor cells (NPC), oligodendrocyte precursor cells (OPC), and astrocytic precursor cells (APC), have been proposed as potential candidates for initiating GB (Fig. 2) [9, 29, 30]. Moreover, emerging evidence indicates that the cell lineage plays a crucial role in determining the molecular subtype of GB. Indeed, the introduction of identical driver mutations in different precursor cells leads to the development of distinct molecular subtypes [11, 12]. Studies have demonstrated that neural stem cells (NSC) in the subventricular zone carry the driver mutations responsible for GB, suggesting them as a potential cell of origin [10, 31, 32]. Further supporting this notion, single-cell RNA-sequencing (scRNAseq) studies have identified profiles resembling NPC, OPC, and APC, providing evidence for a neuronal/glial origin of GB [8, 33]. However, the cellular origin of GB with mesenchymal features, despite the well-described mesenchymal transcriptomic profile, remains elusive. The hypothesis of pMSC as GB-initiating cells will be discussed further (Fig. 2).
To support the hierarchical development model, CD133+ glioma stem cells (GSC) have been identified within GB tumors. These GSC exhibit remarkable proliferation capacity, self-renewal abilities, and differentiation potential [34, 35]. They are characterized by the expression of CD133, OCT4, CD44, nestin, and SOX2, although a specific marker exclusive to GSC has not yet been identified [34, 36, 37]. GSC are described as slow-dividing or quiescent cells that reside in protective microenvironments called GSC niches, contributing to intratumoral heterogeneity and therapy resistance [34, 38, 39]. GSC preferentially reside in the perivascular niche, interacting with endothelial cells in intricate bidirectional crosstalk, and in the perinecrotic niche (Fig. 3) .
GB immune microenvironment
GB is a highly complex tissue composed of tumor cells and their surrounding microenvironment which supports tumor growth through a permissive neighborhood. The tumor microenvironment (TME) consists of cells (including immune cells, vascular cells, glial and neuronal cells, and stem cells), soluble factors, signaling molecules, and an extracellular matrix. It is a dynamic milieu considered to play an active role in tumorigenesis through reciprocal communication with cancer cells . GB TME is compartmentalized in tumor niches which are critical regions where interactions between cancer cells and host cell populations are promoted (Fig. 3).
One of the main features of GB is microvascular proliferation. The tumor vasculature plays a crucial role in supporting tumor growth through various mechanisms, including:
Angiogenesis This is the primary process involved in GB vascularization, triggered by the release of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), by tumor cells.
Vessel co-option Tumor cells possess the ability to migrate along existing blood vessels, enabling invasion of the brain through vascular routes .
Vasculogenesis This process involves the recruitment of endothelial cell progenitors derived from the bone marrow, contributing to the assembly of neo-vessels .
Immune cells may represent up to 50% of the GB tumor bulk . Among these immune cells, tumor-associated macrophages (TAM) are the predominant population and are characterized by their origin, localization, and functions, encompassing both microglia and bone marrow-derived macrophages (BMDM) [49,50,51]. Notably, BMDMs represent approximately 85% of TAM and are primarily found in perivascular regions within the tumor, while microglia are localized in peri-tumoral areas [51, 52].
TAM can exhibit different activation states depending on environmental cues, polarizing into either type I response (M1 TAM) or type II response (M2 TAM) through classical or alternative activation, respectively. M1 TAM promote inflammation by producing pro-inflammatory cytokines, such as IL- 12, IL-1β, TNF-α, IL-6, and IL-23, while M2 TAM suppress inflammation by producing ARG1, IL-10 and IL-4 . Initially, once recruited within the GB TME, TAM were considered to polarize toward an M2-like phenotype that promotes invasion, angiogenesis and immunosuppression [54,55,56]. However, recent studies have revealed that TAM encompass a dynamic entity that includes antitumoral M1-like, pro-tumoral M2-like, and non-polarized M0 phenotypes [27, 57].
Regarding GB molecular subtypes, mesenchymal GB exhibit higher AIF1 expression (encoding for IBA1), a marker associated with TAM . These findings is consistent with previous studies showing increased infiltration of TAM in NF1-altered GB [7, 58]. In addition, it has been suggested that PMT was associated with increased TAM infiltration .
Functionally, TAM play a pivotal role in gliomagenesis through complex cross-talk with tumor and TME cells, contributing to tumor progression, immunosuppression, and cerebral edema . TAM release factors such as TGFβ, IL-1β, IL-6, stress-inducible protein 1 (STI1), and epidermal growth factor (EGF) that stimulate tumor growth and invasion (Fig. 3) [60,61,62,63]. In addition, their immunosuppressive role includes the recruitment of CD4+ /FOXP3+ T regulatory (Treg) cells and myeloid-derived suppressor cells (Fig. 3) [64, 65]. Furthermore, due to their perivascular localization, TAM have been investigated for their involvement in cerebral edema. Studies have shown that dexamethasone, commonly used for the management of cerebral edema, inhibits TAM production of IL-1β, and genetic ablation of IL-1α/β or IL-1β in a murine GB model or the administration of a potential IL-1β inhibitor (Sulfasazaline) reduces cerebral edema [66, 67]. The potential role of TAM in vasogenic cerebral edema underscores the need for further investigations into the complex interaction of TAM with the components of the blood–brain barrier (BBB).
These findings point out the crucial role of the perivascular niche in gliomagenesis, by promoting angiogenesis, modulating the immune response, supporting tumor cell invasion, and providing a stem cell niche. Within this niche, pMSC are also present, and their role in GB development and progression will be discussed below.
Perivascular mesenchymal stromal in the CNS
First identified in the bone marrow (BM) and termed colony-forming unit fibroblasts (CFU-F), MSC are characterized in vitro by a spindle-shaped, fibroblast-like, plastic-adherent appearance [68, 69]. They are multipotent progenitor cells that have the ability to differentiate into adipocytes, chondrocytes, and osteoblasts [70,71,72]. Their multipotency has raised much interest in tissue engineering research for using culture-expanded MSC to replace injured or damaged mesenchymal tissue . MSC express CD105 (Endoglin), CD73, and CD90 (Thy1) and lack the expression of CD45, CD34, CD14 or CD11b, CD79a or CD19, and HLA-DR [70, 71, 74]. Other markers, such as CD140b (PDGFRB), CD271 (Low-affinity NGF receptor), CD146 (Muc18), and CD248 have been suggested to identify MSC [75,76,77,78] but these markers are equally expressed by PC. As the concept of MSC was initially defined as a multipotent cell residing within the BM, it has evolved over the years to a wide concept that includes multipotent perivascular cells of any organ, including the CNS, as discussed below.
Origin of pMSC and PC in the CNS vasculature
MSC in adult tissues have two main embryonic origins, deriving either from the mesoderm or the NC [79,80,81,82,83]. During embryogenesis, MSC migrate along vessels and then reside in the perivascular niche of all adult tissues, adopting similar features to that of PC [80, 84].
The term ‘PC’ is often used in the literature to refer to microvascular periendothelial cells . The accepted definition of a PC is a cell that is embedded within the vascular basement membrane, as observed by electron microscopy. However, because ultrastructural analyses are impractical, most published papers may not differentiate PC from other periendothelial cells, including vSMC and pMSC [14, 86,87,88,89,90,91]. It is now clear that different cell types exist in the periendothelial compartment but accurately identifying their phenotypes remains a challenge. PC cannot be definitively identified and distinguished from vSMC or pMSC using a single molecular marker. Commonly applied markers or genes (Table 2), such as NG2/Cspg4, CD13/Anpep, and desmin, are not specific and their expression is not stable, particularly in disease conditions. Other markers, such as CD248 (endosialin) and CD90 (Thy-1), are highly expressed by PC but recent investigations revealed that they are also expressed by pMSC, especially in the context of GBM . In addition, it has been demonstrated that PC, originally defined by their vascular mural localization, have the same osteogenic, adipogenic, and myogenic potential as MSC and also express surface markers of MSC, such as CD44, CD73, CD90, and CD105 in vitro [80, 92].
Recent studies utilizing cell lineage tracing and single-cell RNA sequencing experiments have provided insights into the role of pMSC cells in the CNS. Garcia et al. have identified 11 cell subtypes within the human CNS vasculature, including three distinct subtypes of pMSC (referred to as vFB in this study), with specific markers (Table 2) . Type I pMSC in humans appear to be primarily involved in extracellular matrix (ECM) organization and fibrosis, while type III cells express various growth factors, including VEGFA. Interestingly, the gradient of gene expression from type I to type II pMSC was continuous with a subpopulation of pericytes, suggesting a potential lineage from type I to type II to PC . Two of the pMSC subtypes align with the subtypes previously identified in mice by Vanlandewijck et al. (referred to as vFB in this study, type I and II) . Similar findings were observed in a zebrafish study, which demonstrated the stem cell potential of pMSCs to transdifferentiate into PC .
Physiological functions of PC and pMSC in the CNS.
The close association between PC and endothelial cells contributes to the formation of the BBB, the maintenance of vascular stability, and the regulation of vascular tone [103,104,105]. Other functions have been described, including a role in angiogenesis and immune regulation properties, making pMSC key players in brain homeostasis and disease. Together with endothelial cells, astrocytes and neurons, they form the neurovascular unit that supplies nutrients and oxygen through the BBB and provides an optimal environment for NSC (as well as GSC) homing and proliferation (Fig. 4) [106, 107].
Many studies have demonstrated the ability of MSC to differentiate toward a neuronal/glial phenotype in vitro and therefore, have suggested a potential role of MSC in brain repair [108,109,110,111,112]. However, while transplantation of MSC in brain and spinal cord injury models tends to improve the functional outcome, the transformation of MSC into neurons/glial cells in vivo is rare and partly results from the fusion of MSC with brain cells [113,114,115,116]. Consequently, it has been suggested that the role of MSC in brain injury mostly relies on their immune regulation properties rather than their neuronal differentiation ability. In fact, this paradigm shift in which MSCs exert healing effects not through their differentiation abilities but rather through their immune modulation functions, has been observed in many therapeutic contexts [117,118,119,120].
Recent findings suggest that pMSC and PC may have a unique ability to monitor the microenvironment of injured tissues. Indeed, it has been demonstrated that they secrete a large number of chemokines, cytokines, and other soluble factors [120,121,122,123]. Their role in immune regulation has initially been highlighted by the observations of prolonged skin graft survival, improvement in severe graft-versus-host disease, and therapeutic effects in an experimental autoimmune encephalomyelitis mouse model [124,125,126]. Indeed, MSC can modulate effector T-cell activation and proliferation, directly through soluble factors or indirectly by controlling the activity of regulatory T-cells (Treg). MSC are also able to control the proliferation and the activation of monocytes/macrophages, natural killer T-cells, dendritic cells, B-cells, and neutrophils, by the secretion of soluble factors such as IFN gamma, nitric oxide (NO), indoleamine 2,3-dioxygenase (IDO), prostaglandin E2 (PGE2), TGFβ, and IL10 [127, 128]. Consequently, MSC have a major role in the coordination of healing responses and the prevention of autoimmunity [119, 127,128,129].
Scar formation is a ubiquitous healing mechanism that is preserved throughout the CNS. Initially, the CNS scar has been referred to as the glial scar as a whole. The glial scar predominantly consists of reactive astrocytes and proteoglycans (heparan sulphate proteoglycan, dermatan sulphate proteoglycan, keratan sulphate proteoglycan and chondroitin sulphate proteoglycan) that stabilize injured CNS tissue by modulating the inflammatory response, yet prevent tissue regeneration [130,131,132]. The glial scar circumscribes the lesion core where the inflammatory response leads to a fibrotic scar, composed of immune cells, fibroblasts, fibronectin, collagen and laminin . It is commonly accepted that fibroblasts are absent in the CNS parenchyma and it has been suggested that they are restricted to the vascular and meningeal niches . Several studies have underscored the role of pMSC and PC in generating the fibrotic scar in the CNS [100, 135,136,137]. In response to spinal cord injury, PC proliferate locally and give rise to myofibroblasts, generating the fibrotic scar . A rapid pMSC/PC loss after cerebral ischemia in human stroke has been observed, with subsequent proliferation of resident PDGFRβ + CD13 + stromal cells that transform to αSMA + CD105 + myofibroblasts . These findings suggest the critical role of the endothelial cell-pMSC/PC interaction to maintain pMSC and PC in a quiescent state to prevent fibrosis.
pMSC in GB
In GB, pMSC can be recruited either from local brain sources, in the perivascular niches, or from the BM by MSC homing to the GB TME [138, 139]. pMSC may also result from GSC differentiation. As discussed above, GSC predominantly reside in perivascular niches and interact with endothelial cells in a bidirectional manner . First reports have suggested that GSC may transdifferentiate into endothelial cells but it has been shown that endothelial cells do not harbor molecular alterations of GB [44, 140,141,142]. In addition, the ability of GSC to undergo mesenchymal differentiation has raised the hypothesis of GSC transdifferentiating into pMSC rather than endothelial cells [143, 144]. Furthermore, it has been demonstrated that GSC generate PC, which may carry the same genetic alterations of GB, such as EGFR amplification, chr 10 loss and PTEN loss .
As discussed above, the origin of mesenchymal GB remains elusive and until recently, an alternative non-neural progenitor cell has not been explored. Indeed, deep scRNAseq of GB progenitor cells uncovered two principal cell-lineage profiles, NC perivascular and radial glia (and its progenies) . Consistently, introducing driver mutations in perivascular cells was sufficient to initiate brain tumors in vivo. In addition, it has been shown that GB of a perivascular lineage represent 44% of the mesenchymal GB subtype and showed significant poorer survival than those of radial glia-lineage . These results suggest that the mesenchymal signature results, at least partially, from pMSC transformation. Indeed, the mesenchymal subtype can be induced by other factors such as the influence TME, the accumulation of mutations in tumor cells (particularly NF1 mutation) and the therapy-induced mesenchymal transition (Fig. 5) .
Several studies have demonstrated the involvement of PC and pMSC in GB tumor vasculature development through a vascular mimicry mechanism [46, 47, 139, 147, 148]. It has also been shown that pMSC overexpress several proteins involved in the promotion of tumor angiogenesis, including CSPG4/NG2, CRYAB, CNN1, CALD1, and VASP, and secrete high levels of angiogenic factors such as SDF-1/CXCL12 and HGF .
The role of pMSC in immune regulation during GB progression was demonstrated by the high levels of anti-inflammatory cytokines (IL-10 and TGFβ) detected in vitro and in vivo in pMSC (referred as to PC in this study) that interact with GB cells . In contrast, after activation by GB cells, pMSC did not produce proinflammatory cytokines, such as IL-1, IL-23, and IL-12 . These observations suggest an immunosuppressive response of pMSC to interaction with GB cells.pMSC also have a tumor growth-enhancing and tumor invasiveness-increasing role [138, 151]. It has been demonstrated that pMSC secrete TGFβ1, stimulating GB cell proliferation and viability through paracrine effect . pMSC are also capable of enhancing GB cell proliferation under direct cell–cell contact, independently of TGFβ1 levels, in vitro and in vivo . Similarly, it has been shown that pMSC secrete IL-6, increasing proliferation and self-renewal of GSC in vitro and enhancing GSC tumorigenicity in vivo (Fig. 3) .
Studies have isolated two subpopulations of pMSC (CD90high pMSC and CD90low pMSC) and have described specific roles in GB progression [154, 155]. It has been observed that CD90low pMSC are more abundant than CD90high pMSC and that CD90low pMSC contribute to angiogenesis and CD90high pMSC promote GB cell growth both in vivo and in vitro [155, 156]. Indeed, CD90low pMSC were shown to produce higher levels of angiogenic factors, such as VEGF, bFGF and IL-6, and CD90high pMSC to produce higher levels of growth factors, such as SDF-1α, CCL5 and MMP9 .
Perivascular and intratumoral cells that co-express PDGFRβ and fibroblast activation protein α (FAP), a common marker used to identify cancer-associated fibroblasts (CAF), were identified in GB . Proteomic quantitative analysis has also demonstrated that pMSC expressed high levels of CAF markers, such as CD146, S100A4/FSP1, nestin, and NG2 . These findings suggest that pMSC, mirroring their transition to myofibroblasts in the context of fibrotic scar, may give rise to CAF that support tumor progression with the GB TME, as described in other solid cancers [158, 159].
pMSC exert pro-tumoral effects, promoting angiogenesis, tumor proliferation and invasiveness, and immunosuppression, in agreement with the observation that increased percentages of pMSC within high-grade gliomas are associated with worse clinical outcome . Recent studies suggest that, in addition to their activities to support GB growth, pMSC may be the cell of origin of GB, particularly the mesenchymal GB subtype . This alternative paradigm provides exciting new research avenues to characterize pMSC in the context of GB and understand better the gliomagenesis.
Availability of data and materials
Acyl-CoA synthetase bubblegum family member 1
Allograft inflammatory factor 1
Astrocytic precursor cells
Bone marrrow-derived macrophage
C-C motif chemokine ligand
Cyclin-dependent kinase 4
Cyclin-dependent kinase 6
Cyclin-dependent kinase inhibitor 2A
Fibroblastic colony forming units
Chitinase 3 like 1
Central nervous system
Collagen type I alpha 1
Collagen type I alpha 2
Crystallin alpha B
Colony stimulating factor 1
Epidermal growth factor
Epidermal growth factor receptor
Erb-b2 receptor tyrosine kinase 3
Fibroblast activation protein-α
Fibroblast growth factor receptor 3
Forkhead box P3
Glioma-CpG island methylator phenotype
Glioma stem cell
Hepatocyte growth factor
Ionized calcium binding adaptor molecule 1
Potassium voltage-gated channel modifier subfamily F member 1
Mitogen-activated protein kinase
Mouse double minute 2
Mouse double minute 4
Mesenchymal-epithelial transition factor
Matrix metallopeptidase 9
Neurofibromatosis type 1
Neural/glial antigen 2
Neural precursor cells
Neural stem cells
Octamer-binding transcription factor 4
Oligodendrocyte precursor cells
Purinergic receptor P2X 7
Platelet-derived growth factor receptor
Platelet endothelial cell adhesion molecule 1
Perivascular mesenchymal stromal cell
Proneural to mesenchymal transition
S100 calcium-binding protein A
Stromal cell-derived factor 1
Smooth muscle actin
SRY-box transcription factor 10
SRY-box transcription factor 2
Telomerase reverse transcriptase
Transforming growth factor beta
Triggering receptor expressed on myeloid cells 1
Triggering receptor expressed on myeloid cells 2
Vascular endothelial growth factor
Vascular endothelial growth factor receptor
Vascular fibroblast (or perivascular fibroblast)
World Health Organization
WHO Classification of Tumours Editorial Board (2021) World Health Organization Classification of Tumours of the Central Nervous System [Internet]. 5th ed. International Agency for Research on Cancer, Lyon [cited 2022 Aug 17]. Available from: https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/Central-Nervous-System-Tumours-2021
Ostrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS (2021) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2014-2018. Neuro-Oncol 23: iii1–iii105
Brennan CW, Verhaak RGW, McKenna A, Campos B, Noushmehr H, Salama SR et al (2013) The somatic genomic landscape of Glioblastoma. Cell 155:462–477
Sturm D, Bender S, Jones DTW, Lichter P, Grill J, Becher O et al (2014) Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nat Rev Cancer 14:92–107
Verhaak RGW, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110
Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD et al (2006) Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9:157–173
Wang Q, Hu B, Hu X, Kim H, Squatrito M, Scarpace L et al (2017) Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment. Cancer Cell 32:42-56.e6
Neftel C, Laffy J, Filbin MG, Hara T, Shore ME, Rahme GJ et al (2019) An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell 178:835-849.e21
Liu C, Sage JC, Miller MR, Verhaak RGW, Hippenmeyer S, Vogel H et al (2011) Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 146:209–221
Alcantara Llaguno S, Chen J, Kwon C-H, Jackson EL, Li Y, Burns DK et al (2009) Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell 15:45–56
Alcantara Llaguno S, Sun D, Pedraza AM, Vera E, Wang Z, Burns DK et al (2019) Cell-of-origin susceptibility to glioblastoma formation declines with neural lineage restriction. Nat Neurosci 22:545–555
Wang Z, Sun D, Chen Y-J, Xie X, Shi Y, Tabar V et al (2020) Cell lineage-based stratification for glioblastoma. Cancer Cell 38:366-379.e8
Hu Y, Jiang Y, Behnan J, Ribeiro MM, Kalantzi C, Zhang M-D et al (2022) Neural network learning defines glioblastoma features to be of neural crest perivascular or radial glia lineages. Sci Adv 8:eabm6340
Garcia FJ, Sun N, Lee H, Godlewski B, Mathys H, Galani K et al (2022) Single-cell dissection of the human brain vasculature. Nature 603:893
Wrensch M, Minn Y, Chew T, Bondy M, Berger MS (2002) Epidemiology of primary brain tumors: current concepts and review of the literature. Neuro-Oncology 4:278–299
Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE et al (2014) The epidemiology of glioma in adults: a “state of the science” review. Neuro- Oncology 16:896–913
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996
Tan AC, Ashley DM, López GY, Malinzak M, Friedman HS, Khasraw M (2020) Management of glioblastoma: state of the art and future directions. CA Cancer J Clin 70:299–312
McLendon R, Friedman A, Bigner D, Van Meir EG, Brat DJ, M. Mastrogianakis G, et al (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068
Singh D, Chan JM, Zoppoli P, Niola F, Sullivan R, Castano A et al (2012) Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 337:1231–1235
Behnan J, Stangeland B, Hosainey SA, Joel M, Olsen TK, Micci F et al (2017) Differential propagation of stroma and cancer stem cells dictates tumorigenesis and multipotency. Oncogene 36:570–584
Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP et al (2010) Identification of a CpG Island methylator phenotype that defines a distinct subgroup of Glioma. Cancer Cell 17:510–522
Sturm D, Witt H, Hovestadt V, Khuong-Quang D-A, Jones DTW, Konermann C et al (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22:425–437
Bhat KPL, Balasubramaniyan V, Vaillant B, Ezhilarasan R, Hummelink K, Hollingsworth F et al (2013) Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma. Cancer Cell 24:331–346
Doucette T, Rao G, Rao A, Shen L, Aldape K, Wei J et al (2013) Immune heterogeneity of glioblastoma subtypes: extrapolation from the cancer genome atlas. Cancer Immunol Res 1:112–122
Engler JR, Robinson AE, Smirnov I, Hodgson JG, Berger MS, Gupta N et al (2012) Increased microglia/macrophage gene expression in a subset of adult and pediatric astrocytomas. PLoS One 7:e43339
Gabrusiewicz K, Rodriguez B, Wei J, Hashimoto Y, Healy LM, Maiti SN, et al. (2016) Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype. JCI Insight [Internet]. [cited 2022 Aug 19]. Available from: https://insight-jci-org.proxy.insermbiblio.inist.fr/articles/view/85841
Kaffes I, Szulzewsky F, Chen Z, Herting CJ, Gabanic B, Velázquez Vega JE et al (2019) Human mesenchymal glioblastomas are characterized by an increased immune cell presence compared to proneural and classical tumors. OncoImmunology 8:e1655360
Holland EC, Hively WP, DePinho RA, Varmus HE (1998) A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice. Genes Dev 12:3675–3685
Friedmann-Morvinski D, Bushong EA, Ke E, Soda Y, Marumoto T, Singer O et al (2012) Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science 338:1080–1084
Sanai N, Alvarez-Buylla A, Berger MS (2005) Neural stem cells and the origin of gliomas. N Engl J Med 353:811–822
Lee JH, Lee JE, Kahng JY, Kim SH, Park JS, Yoon SJ et al (2018) Human glioblastoma arises from subventricular zone cells with low-level driver mutations. Nature 560:243–247
Bhaduri A, Di Lullo E, Jung D, Müller S, Crouch EE, Espinosa CS et al (2020) Outer radial glia-like cancer stem cells contribute to heterogeneity of glioblastoma. Cell Stem Cell 26:48-63.e6
Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T et al (2004) Identification of human brain tumour initiating cells. Nature 432:396–401
Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828
Alameda F, Velarde JM, Carrato C, Vidal N, Arumí M, Naranjo D et al (2019) Prognostic value of stem cell markers in glioblastoma. Biomarkers 24:677–683
Arai H, Ikota H, Sugawara K, Nobusawa S, Hirato J, Nakazato Y (2012) Nestin expression in brain tumors: its utility for pathological diagnosis and correlation with the prognosis of high-grade gliomas. Brain Tumor Pathol 29:160–167
Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB et al (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760
Chen J, Li Y, Yu T-S, McKay RM, Burns DK, Kernie SG et al (2012) A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488:522–526
Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B et al (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11:69–82
Broekman ML, Maas SLN, Abels ER, Mempel TR, Krichevsky AM, Breakefield XO (2018) Multidimensional communication in the microenvirons of glioblastoma. Nat Rev Neurol 14:482–495
Seano G, Jain RK (2020) Vessel co-option in glioblastoma: emerging insights and opportunities. Angiogenesis 23:9–16
Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L et al (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7:1194–1201
Soda Y, Marumoto T, Friedmann-Morvinski D, Soda M, Liu F, Michiue H et al (2011) Transdifferentiation of glioblastoma cells into vascular endothelial cells. Proc Natl Acad Sci U S A 108:4274–4280
Zhao C, Gomez GA, Zhao Y, Yang Y, Cao D, Lu J et al (2018) ETV2 mediates endothelial transdifferentiation of glioblastoma. Signal Transduct Target Ther 3:4
El Hallani S, Boisselier B, Peglion F, Rousseau A, Colin C, Idbaih A et al (2010) A new alternative mechanism in glioblastoma vascularization: tubular vasculogenic mimicry. Brain J Neurol 133:973–982
Scully S, Francescone R, Faibish M, Bentley B, Taylor SL, Oh D et al (2012) Transdifferentiation of glioblastoma stem-like cells into mural cells drives vasculogenic mimicry in glioblastomas. J Neurosci 32:12950–12960
Zhang P, Miska J, Lee-Chang C, Rashidi A, Panek WK, An S et al (2019) Therapeutic targeting of tumor-associated myeloid cells synergizes with radiation therapy for glioblastoma. Proc Natl Acad Sci 116:23714–23723
Klemm F, Maas RR, Bowman RL, Kornete M, Soukup K, Nassiri S et al (2020) Interrogation of the microenvironmental landscape in brain tumors reveals disease-specific alterations of immune cells. Cell 181:1643-1660.e17
Bowman RL, Klemm F, Akkari L, Pyonteck SM, Sevenich L, Quail DF et al (2016) Macrophage ontogeny underlies differences in tumor-specific education in brain malignancies. Cell Rep 17:2445–2459
Chen Z, Feng X, Herting CJ, Garcia VA, Nie K, Pong WW et al (2017) Cellular and molecular identity of tumor-associated macrophages in glioblastoma. Cancer Res 77:2266–2278
Müller S, Kohanbash G, Liu SJ, Alvarado B, Carrera D, Bhaduri A et al (2017) Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment. Genome Biol 18:1–14
Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32:593–604
Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23:549–555
Gutmann DH, Kettenmann H (2019) Microglia/brain macrophages as central drivers of brain tumor pathobiology. Neuron 104:442–449
Ah-Pine F, Malaterre-Septembre A, Bedoui Y, Khettab M, Neal JW, Freppel S et al (2023) Complement activation and up-regulated expression of anaphylatoxin C3a/C3aR in glioblastoma: deciphering the links with TGF-β and VEGF. Cancers 15:2647
Landry AP, Balas M, Alli S, Spears J, Zador Z (2020) Distinct regional ontogeny and activation of tumor associated macrophages in human glioblastoma. Sci Rep 10:19542
Sørensen MD, Dahlrot RH, Boldt HB, Hansen S, Kristensen BW (2018) Tumour-associated microglia/macrophages predict poor prognosis in high-grade gliomas and correlate with an aggressive tumour subtype. Neuropathol Appl Neurobiol 44:185–206
Buonfiglioli A, Hambardzumyan D (2021) Macrophages and microglia: the cerberus of glioblastoma. Acta Neuropathol Commun 9:1–21
Coniglio SJ, Eugenin E, Dobrenis K, Stanley ER, West BL, Symons MH et al (2012) Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling. Mol Med 18:519–527
Carvalho da Fonseca AC, Wang H, Fan H, Chen X, Zhang I, Zhang L et al (2014) Increased expression of stress inducible protein 1 in glioma-associated microglia/macrophages. J Neuroimmunol 274:71–77
Ye X, Xu S, Xin Y, Yu S, Ping Y, Chen L et al (2012) Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-β1 signaling pathway. J Immunol 189:444–453
Feng X, Szulzewsky F, Yerevanian A, Chen Z, Heinzmann D, Rasmussen RD et al (2015) Loss of CX3CR1 increases accumulation of inflammatory monocytes and promotes gliomagenesis. Oncotarget 6:15077–15094
Gielen PR, Schulte BM, Kers-Rebel ED, Verrijp K, Petersen-Baltussen HMJM, ter Laan M et al (2015) Increase in both CD14-positive and CD15-positive myeloid-derived suppressor cell subpopulations in the blood of patients with glioma but predominance of CD15-positive myeloid-derived suppressor cells in glioma tissue. J Neuropathol Exp Neurol 74:390–400
Chang AL, Miska J, Wainwright DA, Dey M, Rivetta CV, Yu D et al (2016) CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory T cells and myeloid-derived suppressor cells. Cancer Res 76:5671–5682
Herting CJ, Chen Z, Maximov V, Duffy A, Szulzewsky F, Shayakhmetov DM et al (2019) Tumour-associated macrophage-derived interleukin-1 mediates glioblastoma-associated cerebral oedema. Brain 142:3834–3851
Sehm T, Fan Z, Ghoochani A, Rauh M, Engelhorn T, Minakaki G et al (2016) Sulfasalazine impacts on ferroptotic cell death and alleviates the tumor microenvironment and glioma-induced brain edema. Oncotarget 7:36021–36033
Caplan A (1991) Mesenchymal stem-cells. J Orthop Res 9:641–650
Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keiliss-Borok IV (1974) Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation 17:331–40
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147
Dominici M, Blanc KL, Mueller I, Slaper-Cortenbach I, Marini FC, Krause DS et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy 8:315–317
da Silva ML, Chagastelles PC, Nardi NB (2006) Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 119:2204–2213
DiMarino AM, Caplan AI, Bonfield TL (2013) Mesenchymal stem cells in tissue repair. Front Immunol 4:201–201
Deans RJ, Moseley AB (2000) Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 28:875–884
Bedoui Y, Lebeau G, Guillot X, Dargai F, Guiraud P, Neal JW et al (2020) Emerging roles of perivascular mesenchymal stem cells in synovial joint inflammation. J Neuroimmune Pharmacol. https://doi.org/10.1007/s11481-020-09958-z
El Agha E, Kramann R, Schneider RK, Li X, Seeger W, Humphreys BD et al (2017) Mesenchymal stem cells in fibrotic disease. Cell Stem Cell 21:166–177
Duffield JS, Lupher M, Thannickal VJ, Wynn TA (2013) host responses in tissue repair and fibrosis. In: Abbas AK, Galli SJ, Howley PM (eds.) Annu Rev Pathol Mech Dis Vol 8 [Internet]. Palo Alto: Annual Reviews; [cited 2022 Jul 16]. p. 241–76. Available from: http://www.webofscience.com/api/gateway?GWVersion=2&SrcAuth=DOISource&SrcApp=WOS&KeyAID=10.1146%2Fannurev-pathol-020712-163930&DestApp=DOI&SrcAppSID=EUW1ED0DFEpvTyL7e8DlqaU8zUdSS&SrcJTitle=ANNUAL+REVIEW+OF+PATHOLOGY%3A+MECHANISMS+OF+DISEASE%2C+VOL+8&DestDOIRegistrantName=Annual+Reviews
Payet M, Ah-Pine F, Guillot X, Gasque P (2023) Inflammatory mesenchymal stem cells express abundant membrane-bound and soluble forms of C-type lectin-like CD248. Int J Mol Sci 24:9546
da Meirelles LS, Caplan AI, Nardi NB (2008) In search of the in vivo identity of mesenchymal stem cells. Stem Cells 26:2287–2299
Crisan M, Yap S, Casteilla L, Chen C-W, Corselli M, Park TS et al (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3:301–313
Takashima Y, Era T, Nakao K, Kondo S, Kasuga M, Smith AG et al (2007) Neuroepithelial cells supply an initial transient wave of MSC differentiation. Cell 129:1377–1388
Le Douarin NM, Creuzet S, Couly G, Dupin E (2004) Neural crest cell plasticity and its limits. Development 131:4637–4650
Majesky MW (2007) Developmental basis of vascular smooth muscle diversity. Arterioscler Thromb Vasc Biol 27:1248–1258
Hungerford JE, Little CD (1999) Developmental biology of the vascular smooth muscle cell: building a multilayered vessel wall. J Vasc Res 36:2–27
Armulik A, Genové G, Betsholtz C (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21:193–215
Vanlandewijck M, He L, Mae MAA, Andrae J, Ando K, Del Gaudio F et al (2018) A molecular atlas of cell types and zonation in the brain vasculature. Nature 554:475
Dorrier CE, Aran D, Haenelt EA, Sheehy RN, Hoi KK, Pintaric L et al (2021) CNS fibroblasts form a fibrotic scar in response to immune cell infiltration. Nat Neurosci 24:234–244
Dorrier CE, Jones HE, Pintarić L, Siegenthaler JA, Daneman R (2022) Emerging roles for CNS fibroblasts in health, injury and disease. Nat Rev Neurosci 23:23–34
Liu J, He L, Muhl L, Mocci G, Gustavsson S, Buyandelger B et al (2021) A human cell type similar to murine central nervous system perivascular fibroblasts. Exp Cell Res 402:112576
Saunders A, Macosko EZ, Wysoker A, Goldman M, Krienen FM, de Rivera H et al (2018) Molecular diversity and specializations among the cells of the adult mouse brain. Cell 174:1015
Zeisel A, Hochgerner H, Lönnerberg P, Johnsson A, Memic F, van der Zwan J et al (2018) Molecular architecture of the mouse nervous system. Cell 174:999-1014.e22
Covas DT, Panepucci RA, Fontes AM, Silva WA, Orellana MD, Freitas MCC et al (2008) Multipotent mesenchymal stromal cells obtained from diverse human tissues share functional properties and gene-expression profile with CD146+ perivascular cells and fibroblasts. Exp Hematol 36:642–654
Rajan AM, Ma RC, Kocha KM, Zhang DJ, Huang P (2020) Dual function of perivascular fibroblasts in vascular stabilization in zebrafish. PLoS Genet 16:e1008800
Caplan AI (2008) All MSCs are pericytes? Cell Stem Cell 3:229–230
Griffiths MR, Botto M, Morgan BP, Neal JW, Gasque P (2018) CD93 regulates central nervous system inflammation in two mouse models of autoimmune encephalomyelitis. Immunology 155:346–355
Brady J, Neal J, Sadakar N, Gasque P (2004) Human endosialin (tumor endothelial marker 1) is abundantly expressed in highly malignant and invasive brain tumors. J Neuropathol Exp Neurol 63:1274–1283
Teicher BA (2019) CD248: a therapeutic target in cancer and fibrotic diseases. Oncotarget 10:993–1009
Bergers G, Song S (2005) The role of pericytes in blood-vessel formation and maintenance. Neuro-Oncology 7:452–464
Berger M, Bergers G, Arnold B, Hämmerling GJ, Ganss R (2005) Regulator of G-protein signaling-5 induction in pericytes coincides with active vessel remodeling during neovascularization. Blood 105:1094–1101
Goritz C, Dias DO, Tomilin N, Barbacid M, Shupliakov O, Frisen J (2011) A pericyte origin of spinal cord scar tissue. Science 333:238–242
Lapenna A, De Palma M, Lewis CE (2018) Perivascular macrophages in health and disease. Nat Rev Immunol 18:689–702
Van Hove H, Martens L, Scheyltjens I, De Vlaminck K, Pombo Antunes AR, De Prijck S et al (2019) A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat Neurosci 22:1021–1035
Díaz-Flores L, Gutiérrez R, Madrid JF, Varela H, Valladares F, Acosta E et al (2009) Pericytes. Morphofunction, interactions and pathology in a quiescent and activated mesenchymal cell niche. Histol Histopathol 24:909–69
Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A, Sutherland BA et al (2014) Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508:55–60
Peppiatt CM, Howarth C, Mobbs P, Attwell D (2006) Bidirectional control of CNS capillary diameter by pericytes. Nature 443:700–704
Goldman SA, Chen Z (2011) Perivascular instruction of cell genesis and fate in the adult brain. Nat Neurosci 14:1382–1389
Tavazoie M, Van der Veken L, Silva-Vargas V, Louissaint M, Colonna L, Zaidi B et al (2008) A specialized vascular niche for adult neural stem cells. Cell Stem Cell 3:279–288
Hermann A, Gastl R, Liebau S, Popa MO, Fiedler J, Boehm BO et al (2004) Efficient generation of neural stem cell-like cells from adult human bone marrow stromal cells. J Cell Sci 117:4411–4422
Zhang H-T, Liu Z-L, Yao X-Q, Yang Z-J, Xu R-X (2012) Neural differentiation ability of mesenchymal stromal cells from bone marrow and adipose tissue: a comparative study. Cytotherapy 14:1203–1214
Zhao L-R, Duan W-M, Reyes M, Keene CD, Verfaillie CM, Low WC (2002) Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp Neurol 174:11–20
Safford KM, Safford SD, Gimble JM, Shetty AK, Rice HE (2004) Characterization of neuronal/glial differentiation of murine adipose-derived adult stromal cells. Exp Neurol 187:319–328
Paul G, Özen I, Christophersen NS, Reinbothe T, Bengzon J, Visse E et al (2012) The adult human brain harbors multipotent perivascular mesenchymal stem cells. PLoS One 7:e35577
Hofstetter CP, Schwarz EJ, Hess D, Widenfalk J, El Manira A, Prockop DJ et al (2002) Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci U S A 99:2199–2204
Chopp M, Li Y (2002) Treatment of neural injury with marrow stromal cells. Lancet Neurol 1:92–100
Borlongan CV, Lind JG, Dillon-Carter O, Yu G, Hadman M, Cheng C et al (2004) Bone marrow grafts restore cerebral blood flow and blood brain barrier in stroke rats. Brain Res 1010:108–116
Weimann JM, Charlton CA, Brazelton TR, Hackman RC, Blau HM (2003) Contribution of transplanted bone marrow cells to Purkinje neurons in human adult brains. Proc Natl Acad Sci U S A 100:2088–2093
Lebeau G, Ah-Pine F, Daniel M, Bedoui Y, Vagner D, Frumence E et al (2022) Perivascular mesenchymal stem/stromal cells, an immune privileged niche for viruses? Int J Mol Sci 23:8038
Prockop DJ (2009) Repair of tissues by adult stem/progenitor cells (MSCs): controversies, myths, and changing paradigms. Mol Ther 17:939–946
Caplan AI, Correa D (2011) The MSC: an injury drugstore. Cell Stem Cell 9:11–15
Prockop DJ (2007) “Stemness” does not explain the repair of many tissues by mesenchymal stem/multipotent stromal cells (MSCs). Clin Pharmacol Ther 82:241–243
Kovac A, Erickson MA, Banks WA (2011) Brain microvascular pericytes are immunoactive in culture: cytokine, chemokine, nitric oxide, and LRP-1 expression in response to lipopolysaccharide ». J Neuroinflamm 8:139
ElAli A, Thériault P, Rivest S (2014) The role of pericytes in neurovascular unit remodeling in brain disorders. Int J Mol Sci 15:6453–6474
Jansson D, Rustenhoven J, Feng S, Hurley D, Oldfield RL, Bergin PS et al (2014) A role for human brain pericytes in neuroinflammation. J Neuroinflamm 11:104
Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I et al (2008) Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet Lond Engl 371:1579–1586
Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S et al (2002) Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 30:42–48
Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E et al (2005) Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106:1755–1761
Singer NG, Caplan AI (2011) Mesenchymal stem cells: mechanisms of inflammation. Annu Rev Pathol Mech Dis 6:457–478
Nauta AJ, Fibbe WE (2007) Immunomodulatory properties of mesenchymal stromal cells. Blood 110:3499–3506
Daniel M, Bedoui Y, Vagner D, Raffray L, Ah-Pine F, Doray B et al (2022) Pathophysiology of sepsis and genesis of septic shock: the critical role of mesenchymal stem cells (MSCs). Int J Mol Sci 23:9274
Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5:146–156
Johnson-Green PC, Dow KE, Riopelle RJ (1991) Characterization of glycosaminoglycans produced by primary astrocytes in vitro. Glia 4:314–321
McKeon RJ, Jurynec MJ, Buck CR (1999) The chondroitin sulfate proteoglycans neurocan and phosphacan are expressed by reactive astrocytes in the chronic CNS glial scar. J Neurosci Off J Soc Neurosci 19:10778–10788
Schreiber J, Schachner M, Schumacher U, Lorke DE (2013) Extracellular matrix alterations, accelerated leukocyte infiltration and enhanced axonal sprouting after spinal cord hemisection in tenascin-C-deficient mice. Acta Histochem 115:865–878
Wyss-Coray T, Feng L, Masliah E, Ruppe MD, Lee HS, Toggas SM et al (1995) Increased central nervous system production of extracellular matrix components and development of hydrocephalus in transgenic mice overexpressing transforming growth factor-beta 1. Am J Pathol 147:53–67
Fernandez-Klett F, Potas JR, Hilpert D, Blazej K, Radke J, Huck J et al (2013) Early loss of pericytes and perivascular stromal cell-induced scar formation after stroke. J Cereb Blood Flow Metab 33:428–439
Soderblom C, Luo X, Blumenthal E, Bray E, Lyapichev K, Ramos J et al (2013) Perivascular fibroblasts form the fibrotic scar after contusive spinal cord injury. J Neurosci 33:13882
Fernandez-Klett F, Priller J (2014) The fibrotic scar in neurological disorders. Brain Pathol 24:404–413
Behnan J, Isakson P, Joel M, Cilio C, Langmoen IA, Vik-Mo EO et al (2014) Recruited brain tumor-derived mesenchymal stem cells contribute to brain tumor progression. Stem Cells 32:1110–1123
Birnbaum T, Roider J, Schankin CJ, Padovan CS, Schichor C, Goldbrunner R et al (2007) Malignant gliomas actively recruit bone marrow stromal cells by secreting angiogenic cytokines. J Neurooncol 83:241–247
Rodriguez FJ, Orr BA, Ligon KL, Eberhart CG (2012) Neoplastic cells are a rare component in human glioblastoma microvasculature. Oncotarget 3:98–106
Kulla A, Burkhardt K, Meyer-Puttlitz B, Teesalu T, Asser T, Wiestler OD et al (2003) Analysis of the TP53 gene in laser-microdissected glioblastoma vasculature. Acta Neuropathol (Berl) 105:328–332
Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T et al (2010) Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468:824–830
deCarvalho AC, Nelson K, Lemke N, Lehman NL, Arbab AS, Kalkanis S et al (2010) Gliosarcoma stem cells undergo glial and mesenchymal differentiation in vivo. Stem Cells 28:181–190
Ricci-Vitiani L, Pallini R, Larocca LM, Lombardi DG, Signore M, Pierconti F et al (2008) Mesenchymal differentiation of glioblastoma stem cells. Cell Death Differ 15:1491–1498
Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu JK et al (2013) Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell 153:139–152
Behnan J, Finocchiaro G, Hanna G (2019) The landscape of the mesenchymal signature in brain tumours. Brain 142:847–866
Birnbaum T, Hildebrandt J, Nuebling G, Sostak P, Straube A (2011) Glioblastoma-dependent differentiation and angiogenic potential of human mesenchymal stem cells in vitro. J Neurooncol 105:57–65
Kong BH, Shin H-D, Kim S-H, Mok H-S, Shim J-K, Lee J-H et al (2013) Increased in vivo angiogenic effect of glioma stromal mesenchymal stem-like cells on glioma cancer stem cells from patients with glioblastoma. Int J Oncol 42:1754–1762
Clavreul A, Guette C, Faguer R, Tétaud C, Boissard A, Lemaire L et al (2014) Glioblastoma-associated stromal cells (GASCs) from histologically normal surgical margins have a myofibroblast phenotype and angiogenic properties. J Pathol 233:74–88
Valdor R, García-Bernal D, Bueno C, Ródenas M, Moraleda JM, Macian F et al (2017) Glioblastoma progression is assisted by induction of immunosuppressive function of pericytes through interaction with tumor cells. Oncotarget 8:68614–68626
Breznik B, Motaln H, Vittori M, Rotter A, Lah TT (2017) Mesenchymal stem cells differentially affect the invasion of distinct glioblastoma cell lines. Oncotarget 8:25482–25499
Rodini CO, da Silva PBG, Assoni AF, Carvalho VM, Okamoto OK (2018) Mesenchymal stem cells enhance tumorigenic properties of human glioblastoma through independent cell-cell communication mechanisms. Oncotarget 9:24766–24777
Hossain A, Gumin J, Gao F, Figueroa J, Shinojima N, Takezaki T et al (2015) Mesenchymal stem cells isolated from human gliomas increase proliferation and maintain stemness of glioma stem cells through the IL-6/gp130/STAT3 pathway. Stem Cells 33:2400–2415
Svensson A, Ramos-Moreno T, Eberstål S, Scheding S, Bengzon J (2017) Identification of two distinct mesenchymal stromal cell populations in human malignant glioma. J Neuro-Oncol 131:245–254
Zhang Q, Yi D-Y, Xue B-Z, Wen W-W, Lu Y-P, Abdelmaksou A et al (2018) CD90 determined two subpopulations of glioma-associated mesenchymal stem cells with different roles in tumour progression. Cell Death Dis 9:1101
Yi D, Xiang W, Zhang Q, Cen Y, Su Q, Zhang F et al (2018) Human glioblastoma-derived mesenchymal stem cell to pericytes transition and angiogenic capacity in glioblastoma microenvironment. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol 46:279–290
Li M, Li G, Kiyokawa J, Tirmizi Z, Richardson LG, Ning J et al (2020) Characterization and oncolytic virus targeting of FAP-expressing tumor-associated pericytes in glioblastoma. Acta Neuropathol Commun 8:1–13
Ligorio M, Sil S, Malagon-Lopez J, Nieman LT, Misale S, Di Pilato M et al (2019) Stromal microenvironment shapes the intratumoral architecture of pancreatic cancer. Cell 178:160-175.e27
Turley SJ, Cremasco V, Astarita JL (2015) Immunological hallmarks of stromal cells in the tumour microenvironment. Nat Rev Immunol 15:669–682
Shahar T, Rozovski U, Hess KR, Hossain A, Gumin J, Gao F et al (2017) Percentage of mesenchymal stem cells in high-grade glioma tumor samples correlates with patient survival. Neuro-Oncol 19:660–668
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This work was supported by the Regional Council of La Réunion, French State and Europe (CPER‐FEDER, GURDTI 2017‐1198‐0002583 VIROPAM) and (CPER‐FEDER 20192211‐0022768, EPIGEN).
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Ah-Pine, F., Khettab, M., Bedoui, Y. et al. On the origin and development of glioblastoma: multifaceted role of perivascular mesenchymal stromal cells. acta neuropathol commun 11, 104 (2023). https://doi.org/10.1186/s40478-023-01605-x