Therapeutic role of caveolin family in stem cell fate and development for management of chronic degenerative diseases: A scientometric study to an in-depth review.

Introduction
Caveolins (CAV), a family of tiny proteins (18–24 kDa), are key components of caveolae membranes, forming caveolae through polymerization. The CAV family includes Caveolin-1 (CAV1), Caveolin-2 (CAV2), and Caveolin-3 (CAV3), each containing an N-terminal tripod domain, a long hairpin transmembrane domain, and a C-terminal domain [1]. CAV and caveolae are present in various cells, including epithelial cells and fibroblasts, where they are crucial for membrane trafficking, lipid composition, and signal transduction [2]. Evidence suggests CAV positively influences stem cell fate [3], as ablation of caveolin genes (CAV1/CAV2/CAV3) leads to an expansion of adult neural stem cell (NSC) populations [4]. This review primarily examines CAV's role with stem cells.
CDD are non-infectious, slow-progressing, and long-lasting conditions like diabetes, heart disease, neurodegenerative diseases and cancer [5]. Their complex cause involved various molecular, cellular, structural, and functional alternations in multiple organs over time [6]. Consequently, the effectiveness of conventional single-targeted treatments is constrained [7]. Recently, stem cell technologies have led to new therapies for various diseases [8]. Adult and pluripotent stem cells, known for self-renewal and differentiation, are promising for regenerative medicine. Nonetheless, cell-based treatments have limitations [9]. To address these challenges, new methods like cell culture with specific biochemical properties and gene editing have emerged. Leveraging CAV's ability to influence signaling pathways and stem cell fate could advance novel therapies and prevention for CDD.
The study of CAV in regulating stem cells for CDD treatment is important but underexplored, warranting a bibliometric analysis. Scientometrics, which uses statistical methods to predict advancements and analyze data trends, is crucial for understanding scientific growth and medical data. Therefore, this review examines CAV's functions in different stem cell types (Table 1), including embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), NSCs, and cancer stem cells (CSCs), and explores stem cell-based therapies for CDD.

Scientometric study

Data and methods

Search and screening of literature
The search query for “Caveolin” and “stem cell” as the topic, was conducted in the Web of Science Core Collection (WOSCC) until December 31, 2024. The study included 335 articles and 39 reviews, excluding irrelevant documents like meeting abstracts, letters, and editorial material, totaling 374 documents (Fig. 1A).

Data download
The raw data were sourced from WOSCC, including full records and cited references in plain text.

Scientometric analysis and visualization
The scientometric data were analyzed with CiteSpace to explore factors like country, institute, keywords, and cited journals. CiteSpace settings included a link retaining factor ( = 3), look back years ( = 5), e for top N (e = 1), time span (2002–2024), years per slice (3), links (strength: cosine, scope: within slices), selection criteria (g-index, k = 25), and pruning (pathfinder-pruning sliced networks). Visualization was done using Microsoft Excel 2019, Origin, VOSviewer, Scimago Graphica, and CiteSpace [10].

General analysis
By December 31, 2024, 374 publications on CAV regulation of stem cells were found in WOSCC, averaging 45.67 citations each. The first article appeared in 2002, and research continues to grow (Fig. 1B).

Country/region and institution analysis
The study analyzed publications from 43 countries, with the USA publishing the most, followed by China, South Korea, and others (Fig. 1D;
Fig. 1E). A total of 655 institutions contributed, with a co-occurrence map showing collaboration networks (Fig. 1C). Larger circles and fonts on the map indicate more publications, while more lines show more collaborations. Top institutions include Thomas Jefferson University and Seoul National University. Most research on CAV's regulatory role on stem cells is conducted in the USA and China, mainly in universities and hospitals.

Journal analysis
Publications appeared in 217 journal types, with the top 10 highlighted in Fig. 1F. Stem Cell Research Therapy led in prominence, sharing the highest publication count with PLoS One, followed by Cell Cycle, Journal of Cellular Physiology, American Journal of Pathology, International Journal of Molecular Sciences, Journal of Biological Chemistry, Stem Cells and Development, Frontiers in Oncology and Journal of Cellular Biochemistry.

Author analysis
Based on WoSCC and CiteSpace, the study identified 545 authors (Fig. 2B), with larger fonts indicating more publications. Cited literature included 725 nodes (Fig. 2E), where larger nodes signify higher citation frequencies. Fig. 2A presents the top 10 authors by publication count, with Lisanti Michael P leading with 13 papers (1.78 %). An author's productivity often reflects their significance in the field. The high citations index (h-index) from Web of Science evaluates both the quantity and quality of academic output, while the median citation percentile indicates influence [11]. Lisanti Michael P was the most influential, with an h-index of 138 and an 86th percentile median citation (Table 2). Fig. 2D shows Razani and Galbiati F as frequently cited authors, with 48 citations (2.3 %), followed by Sotgia F with 45 citations (2.16 %).

Literature and cited reference
Table 3 lists the top 10 most-cited articles of CAV's regulatory effects on stem cells, with article [12] leading at 1069 citations.
Table 4 also highlights the top 10 cited references. Fig. 2C shows a co-occurrence map, where article [4] is cited most frequently, at 9 times. Fig. 2F groups the cited references into 7 clusters, illustrating the foundational knowledge in this field. These publications have been pivotal in identifying key research on CAV's role in stem cell regulation, suggesting that CAV may significantly influence stem cell fate and potentially protect against CDD.

Keyword analysis
Keywords theoretically indicate research trends and hotspots in scientometrics [13]. This review visualizes keywords using a heatmap (Fig. 3A), a time zone map (Fig. 3B) and a clustering timeline view (Fig. 3C). As shown in Fig. 3A, “Cell Biology” is the predominant topic, followed by “Oncology”, “Biochemistry Molecular Biology”, “Pharmacology Pharmacy ” and “Neurosciences Neurology”. Fig. 3B created with CiteSpace, shows each keyword as a node, with larger nodes indicating higher frequency. Node colors reflect the time of appearance, with cooler colors for earlier and warmer colors for later occurrences. The keywords time zone map illustrates the evolution of knowledge over time, highlighting research trends and future directions [14]. While “Caveolin” is a common keyword, most studies focus on CAV1's role in stem cells, with limited research on CAV2/3. Besides CAV1 and stem cells, the keywords activation, proliferation, and differentiation are prevalent. Fig. 3C created using CiteSpace, features 10 significant clusters. The clustering timeline view illustrates each cluster's duration and interconnections, highlighting research evolution. The x-axis represents publication years, while the y-axis indicates cluster numbers. Cluster analysis reveals that research primarily concentrates on stem cells, differentiation, cancer, and the central nervous system (CNS).

CAV family structure and function
Caveolae are 50–100 nm vesicles that form Ω-shaped plasma membrane invaginations crucial for lipid metabolism and complicated intracellular signaling [15]. The main structural protein of caveolae, CAV1/2/3, have been implicated in cell migration, cell cycle and cell polarity, transformation, and signal transduction. The genes encoding the structurally similar proteins CAV1, CAV2, and CAV3, are located on specific regions, with CAV1 and CAV2 on chromosome 7q31.1 and CAV3 on chromosome 3p25 (Fig. 4). CAV1, the most studied, spans 2704 base pairs and has three highly conserved exons across species. It exists in two plasma membrane isoforms, α and β, and functions as a homodimer [16], CAV2 co-localizes and forms hetero-oligomers with CAV1 but cannot independently form pits within caveolae [17]. CAV3, known as M-caveolin, is muscle-specific [18] and structurally distinct from CAV1 [19]. The N and C termini of CAV1 face the cytoplasm, featuring a membrane-embedded hydrophobic domain and a hairpin structure [20]. CAV2 differs with functional domains like a G-protein binding domain and a CSD in its N-terminal region. CAV3 exhibits significant structural and functional similarities to CAV1 and possesses the ability to independently form caveolae [21]. Found in various organs and tissues, including the liver, brain, heart, and lungs, CAV proteins are linked to diseases, including cancer [22], cardiovascular disorders [23], and neurodegenerative diseases [24].

CAV family and embryonic stem cells (ESCs)
ESCs, derived from the inner mass cells or primordial germ cells of early embryos, exhibit the capacity for both self-renewal and differentiation into various cell types and tissues, making them valuable for regenerative medicine and developmental biology. A comprehensive comprehension of the mechanisms underlying ESC pluripotency and self-renewal is crucial for progress in regenerative medicine.
In addition to soluble mitogens, extracellular matrix (ECM) constituents such as collagen, laminin, and fibronectin (FN) play a regulatory role in cell proliferation by serving as binding sites for cells through the integrin family of transmembrane receptors. Notably, CAV is identified as essential for FN-induced ESC proliferation, activating the RhoA-PI3K/AKT-ERK1/2 pathway (Fig. 5A) [25]. Similarly, epidermal growth factor (EGF) enhances ESC proliferation by phosphorylating CAV1, leading to activation of the PI3K/AKT and ERK1/2 pathways (Fig. 5B) [26]. High glucose levels activate CAV1 and INb1, leading to alterations in the focal adhesion signaling pathway and subsequent enhancement of ESC proliferation (Fig. 5C) [27]. Additionally, Estradiol (E2) increases CAV1 and CAV2 expression via PI3K/AKT and ERK pathways, promoting mouse ESC proliferation by affecting cell cycle regulators (Fig. 5D) [28].
These findings underscore the regulatory role of CAV1 in ESC self-renewal and proliferation, warranting further exploration of its role in differentiation. Additionally, CAV2 is implicated in the proliferation of ESCs, but it remains unclear if altering CAV2 alone can regulate the proliferation and differentiation, or if concurrent alterations to both CAV1 and CAV2 are more effectively. Despite there's no direct evidence for CAV3′s role in ESCs, it is noteworthy that CAV3 plays a crucial role in the development of cardiomyocytes (CMs) from ESCs. Specifically, CAV3, a vital component of the cardiac myometrium, exhibits increased expression during the in vitro development of human ESC derived-cardiomyocytes (ESC-CMs) [29]. Moreover, puerarin enhances t-tubule formation in mouse ESC-CMs by downregulating miR-22 and upregulating CAV3 [30]. Therefore, further research is needed to elucidate the specific roles of CAV family members in ESC proliferation and differentiation.

CAV family and adult stem cells

CAV family and mesenchymal stem cells (MSCs)
MSCs are multipotent, enabling them to self-renew and differentiate into specialized cell types within wounded regions, while secreting chemokines, cytokines, and growth factors that facilitate tissue regeneration [31].

Bone marrow mesenchymal stem cells (BMSCs)
BMSCs exhibit multipotent characteristics, with the ability to differentiate into various cell types, such as neurons, fat cells, CMs, and osteoblasts. Furthermore, BMSCs typically act as paracrine sources, secreting growth factors, cytokines, and other bioactive molecules. Cell membranes are crucial barriers and initial contact points for MSCs with their ECM. Changes in membrane components and properties like fluidity and adhesiveness impact cell morphology, movement, migration and communication. Research indicates that knockdown of CAV1 expression or cholesterol depletion in human BMSCs (hBMSCs) decreases caveolae content, increases membrane fluidity, reduces integrin expression, and slows adhesion [32]. This suggests that manipulating MSCs' biological activity through cholesterol and CAV1/caveolae may enhance their application in cell therapy and tissue engineering. Additionally, CAV1 overexpression has been shown to boost BMSC proliferation in vitro and in vivo. Transplanting BMSCs with increased CAV1 expression speeds up healing of deep second-degree burns by boosting growth factors and cytokines in rats [33]. Moreover, using CAV1 siRNA to downregulate CAV1 may enhance BMSCs' differentiation into CMs by inhibiting signal transducer and activator of transcription 3 (STAT3) phosphorylation [34], offering new insights into BMSC differentiation and stem cell therapy for heart repair.
Investigating the CAV family's role in BMSC differentiation could provide new insights into the balance between osteogenesis and adipogenesis within these cells. Notably, Inhibiting CAV1 expression effectively promotes adipogenesis in hBMSCs [35]. Compared to rigid scaffolds, hBMSC grown on flexible scaffolds exhibit lower CAV1 levels, leading to increased YAP/TAZ expression. This facilitates YAP/TAZ translocate to the nucleus and initiates the transcription of genes involved in adipogenesis (Fig. 6A) [35]. CAV1 expression rises in hBMSCs during osteogenic differentiation and is high in terminally differentiated mesenchymal cells [36,37]. Nevertheless, reducing CAV1 with siRNA can boost hBMSC proliferation and osteogenic differentiation [38]. This suggests a need to explore CAV1′s role in MSC lipogenic/osteoblastic differentiation. Notably, Cav1(−/−) BMSCs lack bone sialoprotein and mineralized nodules but show increased osteocyte and osteocalcin expression. Despite dysfunctional osteogenic differentiation, these cells still respond to mechanical stimuli [39]. The variations in the studies may stem from differences in cell species and culture, but it's clear that CAV1 significantly influences BMSC differentiation. This highlights the need to further investigate CAV1′s role in mediating this process. Key questions include:
1) How does CAV1 overexpression affect hBMSC osteogenic differentiation? 2) Given identical conditions, what impact do various CAV1 expression levels (knockout, low, normal, high) have on BMSC proliferation and differentiation? 3) How does CAV modulate the molecules and mechanisms involved in BMSC differentiation and proliferation? Therefore, more in-depth analysis is required to better understand CAV1′s regulatory role and therapeutic potential in MSCs.
CAV3 expression in BMSCs increases during osteogenic induction, and its silencing reduces alkaline phosphatase activity, osteogenic gene expression, and mineral nodule formation in BMSCs with ankyrin repeat domain 1 overexpression [40]. This highlights the crucial role of CAV family in BMSC proliferation and differentiation, providing a novel insight into adipogenesis and bone formation interplay. Moreover, further research is required to elucidate how CAV family and caveolae structures regulate cell signaling, which could advance bone tissue engineering and cell transplantation strategies.

Adipose-derived mesenchymal stem cells (ADSCs)
Human ADSCs (hADSCs) are multipotent stem cells found in adipose tissue, ideal for regenerative medicine [41]. Down-regulating CAV1 expression enhances hADSC differentiation into dopamine-like neurons, increasing tyrosine hydroxylase, Lmx1a, and Nurr1 expression (Fig. 6C), and dopamine release [42]. However, the effect of CAV on hADSCs and the molecular mechanism of CAV1 in promoting this differentiation remain unclear, requiring further study for potential Parkinson's disease (PD) therapy.
CAV1 serves as a key inhibitory factor in the activation of endothelial nitric oxide synthase (eNOS), thereby suppressing Nitric oxide (NO) production [43]. NO is integral to various physiological processes, such as stem cell differentiation and osteogenesis [44]. The interaction between eNOS and CAV1 controls NO levels, affecting Wnt ligand expression. This interaction facilitates the nuclear translocation of β-catenin and the transcription of osteogenic-specific genes, ultimately promoting osteogenic differentiation (Fig. 6B) [45].
Primary hADSCs can proliferate and differentiate into hepatocyte-like cells, with hepatocellular factors enhancing CAV1 expression in a time-dependent manner. During liver differentiation, the mitogen-activated protein kinase (MAPK) signaling pathway is activated, but inhibited when CAV1 is knocked down. This leads to decreased albumin and hepatic nuclear factor 1 alpha expression, suggesting CAV1′s crucial role in regulating hADSCs' hepatocyte-like differentiation via the MAPK pathway [46].
The decline in endogenous stem cell function with age may contribute to the aging process, accompanied by various physiological and pathological alterations. While transplanted MSCs have shown promising therapeutic benefits in wound healing due to their accessibility and versatility, aged MSCs have reduced proliferation and differentiation, hindering their therapeutic effectiveness. Therefore, understanding how CAV family targets regulate MSCs is crucial for enhancing the therapeutic potential in treating CDD before they can be widely used in clinical settings.

CAV family and neural stem cells (NSCs)
Adult NSCs can differentiate into neurons, astrocytes, and oligodendrocytes [47] and are localized in the subventricular area (SVZ) (Fig. 7A) and subgranular zone (SGZ) of the adult brain (Fig. 7B).They possess the intrinsic ability for self-renewal and hold promise for regenerating neural tissue in conditions like PD, AD and stroke [48]. Current therapies focus on either transplanting stem cell or modifying endogenous ones. The CAV family proteins play a key role in determining NSC fate, making their regulation crucial for effective and stable therapies [49].
CAV1 and CAV2 are widely expressed in the brain and influence neurogenesis and axonal growth, potentially regulating NSC proliferation [50] (Fig. 7C). On the one hand, CAV may serve as a critical regulator of adult NSC proliferation. Ablation of CVA1, CAV2, or CAV3 alone promotes NSC proliferation in the SVZ of adult mice [4]. CAV1, a multi-functional regulator of GR in in neural progenitor/stem cells (NPSCs), affects receptor action to impact NPSC proliferation [51]. On the other hand, CAV1 plays an important role in the differentiation of NSCs. Our studies have revealed that CAV1 aids astrocyte differentiation by modulating Notch1/NICD and Hes1 [52], and promotes oligodendrocyte differentiation by reducing β-catenin [53]. Hypoxic neural progenitor cells (NPCs) enhance neuronal development by reducing CAV1, increasing vascular endothelial growth factor (VEGF), and phosphorylating p44/42MAPK compared to normoxic NPCs [54]. CAV1/VEGF signaling also supports exercise-induced NSC migration and neuronal differentiation, ultimately improving neural recovery in ischemic rats [55]. Upregulation of miR-199a-5p inhibits CAV1 expression, boosts VEGF and brain-derived neurotrophic factor (BDNF) levels, ameliorate neurological deficits, reduce infarct size, and promote neurogenesis [56]. Our study has demonstrated that CAV1 derived from brain microvascular endothelial cells (BMVECs) acts as a critical niche regulator to inhibit neurogenesis in post-stroke brains, by modulating VEGF and NeuroD1 signaling pathways [57]. Phosphorylated CAV1 promotes axon growth and early neuronal differentiation in iPSC-derived NPCs. Proper axon growth is crucial for neural network development, and targeting CAV1 could support neuroplasticity after CNS damage [58].
These findings highlight that manipulating the CAV family could be a therapeutic strategy for brain injuries and diseases by regulating NSC self-renewal and differentiation. Exploring the role of CAV in cell communication within the neurogenic niche could improve our understanding of brain plasticity and aid in developing new treatments for neurological disorders. Increased CAV1 and ERα coupling may contribute to Fragile X syndrome (FXS), while reducing CAV1 might enhance cingulate long-term potentiation by boosting GluA1 synaptic incorporation [59]. However, the therapeutic potential of targeting the CAV family for treating FXS through adult neurogenesis remain unclear. More research on the molecular mechanisms of CAV in NSC fate is required to advance therapies for brain injuries and nervous system disorders.

CAV family and cancer stem cells (CSCs)
CSCs are a subset of cancer cells that possess the ability to differentiate and proliferate within tissues [60]. Unlike normal stem cells, CSCs exhibit tumorigenic properties and more resistant to traditional treatments, such as chemotherapy and radiotherapy than 'differentiated' tumor cells. While chemotherapy can initially reduce tumor size, it often fails to completely eliminate CSCs, leading to recurrence [61]. To address this challenge, numerous new treatments targeting CSCs are being developed. Recent research highlights the role of CAV1, a membrane transporter protein, in drug resistance and signaling transduction in stem cells [62]. CAV1, the main structural protein of caveolae, contribute to diverse cellular functions such as energy metabolism and transduction of signaling cascades, including RAS oncogenes pathways [63]. Loss of stromal CAV1 may boost tumor advancement through diverse paracrine signals, including ECM remodeling, fibrosis, and tumor microenvironment.

Breast cancer stem cells (BCSCs)
Breast cancer is the most common cancer in women and the leading cause of cancer-related mortality [64]. BCSCs are crucial in the disease's onset and progression, yet their metabolic characteristics and regulation are not well understood [65]. With rising breast cancer rates, the identification of new anti-cancer strategies and targets is essential.
CAV1 is often down-regulated in BCSCs, associated with a shift from mitochondrial respiration to aerobic glycolysis. CAV1 deficiency is linked to increased breast duct hyperplasia and tumor development. CAV1 may facilitate Von Hippel-Lindau (VHL)-mediated ubiquitination and degradation of c-Myc in BCSCs through the proteasome pathway (Fig. 8) [66]. Following breast cancer chemotherapy, CAV1 expression increases alongside β-catenin and ATP-binding cassette subfamily G member 2 (ABCG2) signaling. Suppressing CAV1 impedes self-renewal while promoting differentiation and sensitizing breast CSCs, achieved through the activation of GSK3β and the inhibition of Akt-mediated β-catenin/ABCG2 pathway [67]. Thus, CAV1 influences chemotherapy resistance in breast CSCs, providing novel therapeutic strategies for CSCs.

Liver cancer stem cells
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, accounting for approximately 70 % to 85 % of primary liver cancers. It is especially prevalent in Asia-Pacific, where it is the 2nd leading cause of cancer death and the 5th most common cancer [68]. Early HCC is best treated with surgery, but there's a high risk of metastasis and recurrence [69]. Advanced HCC often resists treatments like chemoembolization and sorafenib, which have significant side effects. Thus, it is imperative to understand the mechanisms of HCC initiation, progression, and treatment resistance [70]. MiRNAs play a crucial role in in human cancer detection and treatment. Specifically, increased miR-124 levels can inhibit liver CSCs self-renew and tumorigenesis, with lower expression in CD90+ or EpCAM+ liver CSCs. Elevated miR-124 in liver CSCs leads to decreased CAV1 expression, likely due to miR-124′s interaction with CAV1's 3'-UTR [71]. This study highlights the miR-124/CAV1 axis as a putative target for liver CSC treatment and a potential indicator for individuals diagnosed with hepatocellular carcinoma.
Indeed, CAV1 is upregulated in numerous cancers, affecting various cellular processes such as proliferation, apoptosis, migration and invasion. It's a promising biomarker for cancer prognosis during irradiation therapy, although its diagnostic value for radiation response is still under investigation. Additionally, CAV2′s role in cancer is complex, as it can exhibit both inhibitory and promotive effects on tumorigenesis, either in conjunction with CAV1 or independently [72]. It is noteworthy that the potential regulatory role of CAV2 in cancer cell proliferation [73], and anti-tumor effects of reduced CAV3 expression are significant discoveries. However, the direct impact of CAV2 and CAV3 on the proliferation and differentiation of CSCs remains largely unclear. Therefore, further research on the CAV family's regulation of CSCs could have important clinical implications for cancer prevention and treatment.

CAV family and epidermal stem cells (EpiSCs)
Recent research indicates that stem cell transplantation, whether systemic or local, can aid in skin damage repair by enhancing vascular development, endothelial cell transformation, and wound healing [74]. However, a simple stem cell transplant may not be sufficient for curing wounds, necessitating further study of the mechanisms involved [75].
CAV1, exhibits high expression levels across various cell types, is crucial for cellular growth, particularly in ESC, MSC and NSC proliferation and differentiation [76]. In EpiSCs, CAV1 expression is critical for controlling proliferation [77,78]. Overexpressing CAV1 enhances EGF-induced cell proliferation without affecting pluripotency [77]. Additionally, curcumin treatment promotes EGF-induced EpiSC proliferation by upregulating CAV1, which can enhance the burned skin regeneration [78]. EpiSCs continually divide to replenish damaged skin as collagen decreases with age. Analyzing CAV's role in EpiSC fate is crucial for insights into wound healing and reducing skin aging.

CAV family and hematopoietic stem cells (HSCs)
HSCs exhibit pluripotency with the ability to differentiate into various blood cells through self-renewal, maintaining stem cell reservoirs for mature blood cell production [79]. The decline in self-renewal, homing, and differentiation capabilities of aged HSCs heightens the susceptibility to anemia and leukemi [80]. CAV1 plays a crucial role in regulating HSC function; its absence in knockout mice reduces self-renewal and cell regeneration, leading to HSC quiescence and increased reactive oxygen species (ROS) production. CAV1 deficiency instigates alterations in the HSC environment, increasing HSC numbers but hindering their differentiation [81].
Age-related hematopoietic dysfunction is significantly influenced by changes in cellular interactions and intrinsic factors like DNA damage, oxidative stress, and senescence [80]. The presence of CAV1/2/3 in caveolae might help counteract the decline in aging HSCs' function, potentially slowing aging and boosting immune function in the elderly.

Therapeutical roles of CAV family in CDD
CDD are the leading cause of long-term disability and death worldwide, including diseases like AD, PD, diabetes, heart disease, and cancer [82]. The CAV family, especially CAV1, interact with a variety of signal transduction proteins and plays a complex role in diseases progression [83,84]. Identifying treatments that target the CAV family could lead to new drug therapies. Table 5 summarizes drugs that regulate CAV to treat CDD, highlighting the focus on CAV1. For instance, curcumin protects against AD by inactivating the CAV1-GSK-3β pathway, reducing tau hyperphosphorylation [85]. Various treatments, including but not limited to compound monomers, traditional Chinese medicine, and western medicine can influence AD, stroke, diabetes, and cancer by regulating CAV1. However, there is limited research on CAV2, which is often regulated with CAV1. Simvastatin can partially restore CAV1 and CAV2 in rats with severe pulmonary hypertension [86]. CAV3 is primarily involved in heart disease, and Geranylgeranylacetone protects the heart by increasing CAV3 levels [87]. Identifying drug responses to CAV1/2/3 is crucial for developing new treatments and clinical applications. Additionally, recent findings on CAV regulation in stem cells emphasize its therapeutic potential in managing conditions like stroke, diabetes, cancer, PAH, and neurodegenerative diseases (Fig. 9), posing key questions for future research and treatment development.

Alzheimer's disease (AD)
AD is a primary degenerative encephalopathy that typically occurs in older adults, marked by chronic cognitive decline due to neuron and synapse loss. Key symptoms include memory, reasoning, and judgment impairments [88]. Pathological hallmarks include senile plaques, neurofibrillary tangles, and cerebral cortex atrophy with β-amyloid deposits [89]. Currently, the utilization of exogenous stem cells to repair neural circuits is a promising therapeutic strategy [90]. Studies in rodent and aging primates show that transplanting growth factor-secreting NSCs can boost neurogenesis, improve cognition, reduce neuroinflammation, and mitigate tau and β-amyloid pathology [91]. Moreover, while MSC transplantation's ability to inhibit Aβ and tau [92], it has significant limitations. For example, transplanted NSCs often become non-neuronal glial cells; And their restricted neuronal differentiation and glial cell gene ratio in vivo hinder MSCs' effectiveness in replacing neural tissue.
CAV1 is essential for NSC differentiation into neurons via multiple pathways, while the lack of CAV2/3 enhances NSC proliferation. Overall, the CAV family holds promise for advancing stem cell therapy and developing new treatments and preventive strategies for AD.

Parkinson's disease (PD)
PD is a leading chronic neurodegenerative disorder marked by the loss of dopaminergic (DA) neurons in the substantia nigra [93,94]. Transplantation of stem cells in the brain to replace lost DA neurons has huge prospects for PD [95] and hADSCs have demonstrated neuroprotective effects in PD models. During their differentiation into DA neurons, the expression of CAV1 decreases, which enhances markers like TH, Lmx1a and Nurr1, as well as boosts dopamine release [42]. CAV1 plays a crucial regulatory role in this differentiation, and further research could enhance stem cell therapy effectiveness and identify new drug targets for PD treatment.

Stroke
Stroke, a prevalent illness that affects the ischemic and hemorrhagic types of the CNS, leads to damage and cognitive impairments, such as numbness, diplopia, slurred speech, ataxia, non-orthostatic vertigo and memory deficits [96,97]. Ischemic injury triggers neurogenesis, aiding NSCs in repairing damaged neural circuits [98]. However, stroke-induced neurogenesis alone is insufficient for the complete restoration of neurological function. CAV1 plays a multifaceted role in brain damage and repair post-stroke. Our study has demonstrated that CAV1, a component of extracellular vesicle exosomes released by BMVECs, inhibits neuronal differentiation of NPCs during cerebral ischemia–reperfusion injury by regulating NeuroD1 expression and p44/42MAPK phosphorylation [57]. Adult neurogenesis serves as an intrinsic mechanism that facilitates brain recovery post-stroke. Our studies reveal CAV1 regulates NSC differentiation into neurons, oligodendrocytes, and astrocytes via various pathways [[52], [53], [54],57]. Thus, studying how CAV1 affects stroke-induced neurogenesis may uncover new therapies for improving functional rehabilitation.

Heart disease
Heart disease is one of the world's deadliest conditions, largely due to the irreversible loss of cardiac cells [99]. Stem cell technology now allows for the in vitro creation of heart cells, offering new treatment possibilities [100]. Research shows that ESC-CMs can integrate into the heart, aiding in cardiac remodeling and improving function without causing teratomas in animal models [[101], [102], [103]]. However, their electrophysiological and contractile abilities are only partially restored due to their immature structure [104]. Mature sarcomeres and t-tubules are essential for their effective integration and function post-transplantation [105].
During cardiac differentiation of ESCs, puerarin enhances myofibril and sarcomere formation and significantly aids t-tubule development in ESC-CMs. This is accompanied by increased transcription of CAV3, amphiphysin-2, and junctophilin-2, essential for t-tubule formation [30]. CAV3 expression rises notably during human ESC-CM differentiation, suggesting its key role in cardiac maturation [29]. CAV3 supports ESC-CM development and maturation, potentially affecting cardiac conditions like hypertrophy and myocardial infarction. While CAV1 and CAV2 regulate ESC proliferation, their roles in CM differentiation remain unreported. CAV3 is absent in undifferentiated ESCs but is crucial for CM function and maturation during ESC-CM differentiation. Downregulating CAV1 enhances BMSC differentiation into CMs by activating STAT3 signaling, but the roles of CAV2 and CAV3 remain unclear [34]. Further research on the CAV family's impact on stem cell differentiation is needed to improve the safety and efficiency of ESC/MSC-derived CMs and to develop effective cardiac repair therapies.

Pulmonary arterial hypertension (PAH)
PAH is a rare and progressive lung disease characterized by poor arterial remodeling, which increases vascular resistance, strains the right ventricle, and can lead to heart failure. This remodeling involves intimal thickening, medial hypertrophy, outer membrane hyperplasia and abnormal ECM deposition, along with smooth muscle cell proliferation in the pulmonary vasculature [106]. Vasoconstriction results from an imbalance in vasoactive mediators and ongoing dysfunction of pulmonary endothelial cells. In a rat model of PAH, rBMSCs engineered with the eNOS+/−CAV1F92A gene effectively inhibited pulmonary vascular smooth muscle cell proliferation and improved hemodynamics, vascular remodeling, and short-term survival [107]. While CAV1 shows promise in the management of pulmonary hypertension, further investigation is required to completely comprehend the role of the CAV family in stem cell therapy.

Cancer
Cancer, a major public health issue, involves tumors from aberrant cell growth that can spread and harm tissues. Chemotherapy, the main treatment, can extend patient lives but often causes severe side effects like organ damage, gastrointestinal issues, and bone marrow suppression [108]. HCC is a common cancer with rising cases, and drug treatments have significant side effects, while surgery often leads to high metastasis and recurrence rates [109]. Therefore, it is imperative to investigate the diverse etiologies of HCC development, advancement, relapse, and drug resistance. CAV1 promotes liver cancer cell growth, spread, and drug resistance, regulated by miR-124, which inhibits liver CSCs' self-renewal and carcinogenesis. Breast cancer the leading form of cancer in women, highlights the need for new anti-tumor strategies [110]. CAV1 deficiency reduces tumorigenicity and increases chemotherapy sensitivity in breast CSCs [67]. Thus, targeting CAV1 may effectively eradicate CSCs and consequently mitigate a range of malignancies.
CAV's regulatory role in various cancers, such as lung [111], stomach [112], and colon [113], is documented, though less so in CSCs. It can influence cancer cells to develop stem cell traits [114]. Notably, targeting CAV reduces ciprofloxacin's impact on lung CSC markers and spheroid formation, despite no direct CAV1 effect on lung CSCs [115]. Understanding the CAV family's role in CSC biology may be beneficial for the supportive care and development of cancer treatment strategies.

Diabetes
Diabetes is a complex metabolic disease often leading to complications like impaired wound healing, which can result in limb loss and disability [116]. This issue arises from factors disrupting epithelialization and wound closure [117]. Stem cell transplantation, particularly using BMSCs, has shown promise in enhancing wound healing by promoting angiogenesis and altering endothelial cells [118]. CAV3 binds MG53 enhances the therapeutic effects of BMSCs in diabetic wound healing via activating the eNOS/NO signaling pathway [119].
CAV1 is a key structural protein in the cell membrane that regulates EpiSC proliferation and aids wound healing. CAV1 overexpression, combined with MSC transplantation, improves healing in deep second-degree burns [77,78]. However, its impact on MSCs for diabetic wound healing is unknown. Future research should explore the CAV family's potential in treating diabetic wounds to inform clinical practice.

Demyelinating diseases
Multiple Sclerosis (MS) is a CDD of the CNS characterized by inflammation, demyelination and progressive neurodegeneration, primarily involving demyelination and axon loss [120,121]. In the MS brain, intense astrocytic responses to demyelination and neurodegeneration result in the formation of dense glial scars within progressing lesions [122]. NSCs possess the ability to divide and differentiate into glial lineages. CAV1 knockdown may lower β-catenin levels and boost oligodendrocyte growth in NPCs, linked to the Wnt/β-catenin pathway, disrupting oligodendrocyte temporal regulation and development [53]. Investigating the CAV family's role in NPC differentiation and myelination could significantly advance the developments of new therapeutic strategies for demyelinating disorders like MS.

Conclusion and perspectives
This review employs scientometrics to explore how the CAV family influences stem cell regulation, aiming to identify research hotspots. It offers a comprehensive analysis of the CAV family's role in diverse stem cell behaviors, providing new insights into preventing and treating CDD.
Stem cells can acquire functional epigenetic memories, impacting tissue fitness and regenerative medicine [123]. Over the past five years, research on CAV and stem cells has expanded to include various stem cell types and diseases (Fig. 3). Understanding CAV-regulated stem cells could enhance regenerative medicine. This review examines the CAV family's role in regulating the proliferation and differentiation of various stem cells, including ESCs, MSCs, CSCs, NSCs, HSCs, and EpiSCs. The CAV family influences key signaling pathways like Notch1/NICD/Hes1 in NSCs [52], PI3K/AKT/ERK1/2 in ESCs [28], eNOS/NO in MSCs [119], and β-catenin/ABCG2 in CSCs [67], which are crucial for preventing and treating CDD (Table 1). Notably, some research has focused solely on the role of CAV family in stem cells, but more in-depth study of downstream mechanisms is still needed [33,77,78,81]. The CAV family's ability to target diverse mechanisms underscores its potential in stem cell therapy for CDD. Although progress has been made in understanding the role of CAV family in CDD, exploring its functions in stem cells will not only enrich our current knowledge on its regenerative potential but also help us unravel its full therapeutic potential in various CDD when combined with stem cell therapy.
This article has two limitations. First, we only focus on English-language publications, potentially missing findings in other languages. Second, only studies from the WOSCC database were included, so some relevant research might be missing. In addition, this paper highlights the current research limitations on the CAV family and stem cells, suggesting future directions. It questions the effects of completely lacking CAV1/2/3 or specific combinations on NSC behavior, particularly in the SVZ and SGZ [4]. While CAV1/2/3 influence tumor development [124], their regulatory roles on CSCs are not well understood, especially for CAV1 and the mechanisms of CAV2/3. Further research into these mechanisms could lead to breakthroughs in cancer therapy. Despite belonging to the same gene family, CAV1/2/3 have different expression patterns, suggesting varied roles in tissue development and stem cell differentiation. Over the past two decades, CAV2/3's role in stem cells has been underexplored compared to CAV1. Therefore, it’s imperative to explore the unique roles of CAV1/2/3 in various stem cells and their regulatory mechanisms in cell proliferation and differentiation.
In conclusion, future research should focus on understanding CAV family interactions in stem cells to aid regenerative medicine and CDD. Identifying new drug targets and developing effective therapies could expand clinical applications of stem cell treatments influenced by CAV or its downstream targets.

Compliance with ethics requirements
This article does not contain any studies with human or animal subjects.

CRediT authorship contribution statement
Ruishuang Ma: Conceptualization, Investigation, Visualization, Data curation, Formal analysis, Writing – original draft. Shuang Wang: Investigation, Data curation, Formal analysis, Writing – original draft. Yuan-Lu Cui: Visualization, Writing – review & editing. Han Zhang: Conceptualization, Investigation, Writing – review & editing, Project administration. Xiaopeng Chen: Conceptualization, Investigation, Writing – review & editing, Project administration. Jinbing Xie: Conceptualization, Investigation, Writing – review & editing, Project administration. Yue Li: Conceptualization, Investigation, Visualization, Funding acquisition, Writing – original draft, Project administration, Supervision.

Funding
This work was supported by the 10.13039/501100001809National Natural Science Foundation of China (No. 82073832) and the 10.13039/501100004733University of Macau (MYRG-GRG2024-00031-ICMS-UMDF). FDCT operating fund for State Key Laboratory (University of Macau) (No. SKL-QRCM-IRG2023-34; SKL-QRCM-IRG2024027). The Science and Technology Development Fund, Macau SAR (No. 005/2023/SKL) and the Start-up Research Grant of the University of Macau (SRG2023-00050-ICMS).

Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.