While the International Society for Cell & Gene Therapy (ISCT) provides a necessary phenotypic baseline (CD73⁺/90⁺/105⁺ and CD34^-/45^-)^[11,12], these minimal criteria fail to capture the functional diversity inherent in ADSCs. Recent single-cell RNA and assay for transposase-accessible chromatin sequencing (scRNA-seq/ATAC-seq) studies have unmasked this biological noise, revealing that cultured ADSCs are a mosaic of proliferative, functional, and senescent subsets^[13]. The identification of specific clusters like Cluster 6 and biomarkers like basonuclin 2 (BNC2) and high mobility group AT-hook 2 (HMGA2) suggests that future clinical success will depend less on bulk cell quantity and more on the enrichment of high-potency, non-senescent sub-lineages. However, the intrinsic molecular traits governing heightened regenerative capacity often overlap with oncogenic hallmarks. Specifically, the core transcription factors BNC2 and HMGA2, while essential for maintaining the undifferentiated state and proliferative vigor of ADSCs, are frequently implicated in malignant transformation and epithelial-mesenchymal transition. HMGA2, for instance, can promote cancer cells to acquire stem cell-like characteristics by regulating chromatin structure, and enhance their invasive and migratory abilities^[14]. Therefore, aggressive selection for these super-subpopulations warrants rigorous scrutiny to ensure that therapeutic potency does not come at the cost of genomic stability or an increased risk of long-term oncogenicity.

While traditional research emphasized the multi-lineage differentiation potential of ADSCs^[15], contemporary focus has pivoted toward a paracrine-driven model. In this framework, the secretome serves as the primary vehicle for therapeutic delivery^[16,17]. This paracrine dominance is particularly pronounced within wound microenvironments; here, ADSCs modulate the M1-to-M2 macrophage phenotypic transition and facilitate neoangiogenesis through the regulated secretion of vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and interleukin-6 (IL-6)^[18,19]. Furthermore, ADSC-derived exosomes (ADSC-exos) - specifically those harboring bioactive cargo such as miR-378 - provide a robust cell-free mechanism to attenuate oxidative stress and enhance keratinocyte viability^[20]. Such advancements underscore a significant transition toward standardized, off-the-shelf precision regenerative medicine.

Notably, the functional efficacy of ADSCs is not an inherent constitutive attribute but a context-dependent state dictated by the host microenvironment. This phenomenon, characterized by Wang et al. as “reciprocal regulation”, entails the induction of an immunosuppressive phenotypic shift in response to inflammatory cues [e.g., interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α)] via indoleamine 2,3-dioxygenase (IDO) or inducible nitric oxide synthase (iNOS) pathways^[21]. Conversely, deleterious environments - including donor senescence, obesity, or systemic sepsis - can “de-license” these cells, precipitating a transition toward a pro-inflammatory senescence-associated secretory phenotype (SASP)^[22-25]. To circumvent these environmental constraints, emerging bioengineering strategies, such as mitochondrial transplantation for metabolic reprogramming^[26] and the development of smart chimeric antigen receptor (CAR)-modified immunosuppression platforms^[27], aim to transition ADSCs from inert cellular grafts into autonomous, responsive modulators of tissue regeneration.

The clinical application of ADSCs has undergone a strategic shift, moving from direct cellular replacement toward a paracrine-centered model^[9] [Figure 2]. Within this framework, extracellular vesicles (EVs), particularly exosomes, serve as bioactive nanovesicles that mirror the regenerative potential of their parental cells while offering enhanced safety profiles and superior scalability^[28-32]. Distinct from passive biological carriers, ADSC-EVs function as dynamic regulatory units, delivering functional non-coding RNAs (ncRNAs) and proteomic payloads that reprogram the recipient microenvironment through the sophisticated modulation of autophagy. Specifically, ADSC-EVs exhibit context-specific pleiotropy: they can either attenuate myofibroblast transformation by inhibiting TGF-β/Smad2-mediated autophagic flux^[33] or mitigate fibrotic pathology by activating phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)-dependent mitophagy^[34], with the functional outcome being contingent upon the specific pathological cues of the wound environment.

The functional versatility of ADSC-EVs is sustained by a complex repertoire of ncRNAs operating via ceRNA networks. Long non-coding RNAs (lncRNAs), such as H19 and Neat1, function as molecular sponges that sequester microRNAs (miRNAs) to derepress regenerative pathways, including the Wnt/β-catenin and Ulk1-mediated autophagic axes^[35,36]. Consistently, the miRNA profile of ADSC-EVs - further optimized by hypoxic preconditioning - functions as a coordinated toolkit for reversing ischemic stagnation. Upregulated miR-21, miR-126, and miR-31 facilitate high-quality healing by activating the PI3K/AKT signaling cascade, thereby promoting targeted vascularization and keratinocyte migration^[37-39]. Recent identification of circular RNAs adds an additional layer of epigenetic control, modulating the miR-144/signal transducer and activator of transcription 3 (STAT3) axis to resolve chronic inflammation^[29].

Inflammatory priming represents a key mechanism through which the context-dependent properties of ADSCs translate into immunomodulatory effects^{[21,29,31,32]}. ADSC-EVs further reinforce this response by delivering miRNAs and lncRNAs that attenuate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. Moreover, unbiased omics analyses have elucidated pivotal molecular checkpoints, such as epiregulin (EREG) and cystatin A (CSTA). The targeted modulation of these factors by ADSCs correlates with enhanced M2 macrophage infiltration and accelerated re-epithelialization in diabetic foot ulcers (DFUs)^[40].

Optimal tissue restoration necessitates the precise integration of chemotaxis, revascularization, and extracellular matrix (ECM) reorganization. The recruitment of ADSCs is primarily mediated via the stromal cell-derived factor-1α (SDF-1α)/C-X-C motif chemokine receptor 4 (CXCR4)/CXCR7 signaling axis, a pathway amenable to targeted manipulation for enhanced site-specific homing^[41]. Following recruitment, integrin β1/PI3K/AKT signaling contributes to the angiogenic response^[39,42]. Concurrently, ADSC-EVs modulate fibroproliferative dynamics by fine-tuning collagen deposition and regulating matrix metalloproteinases (MMPs)^[28,43]. Specifically, miR-141-3p-mediated suppression of c-Jun N-terminal kinase (JNK)/extracellular signal-regulated kinase (ERK) signaling inhibits myofibroblast differentiation, thereby favoring functional tissue regeneration over hypertrophic scar formation^[44]. This multifaceted regulatory network is further reinforced by the broader ADSC secretome, which preserves ECM structural integrity and attenuates environmental senescence^[43,45].

Autologous fat grafting (AFG) remains the standard for soft tissue restoration, yet it is plagued by a volumetric lottery, with unpredictable resorption rates that range from 10% to 90%^[48]. This phenomenon is primarily driven by delayed neovascularization, which subjects the central graft to lethal ischemic stress^[49].

The identification of ADSCs within the SVF offered a transformative solution^[50]. This catalyzed the advent of CAL, a strategy where lipoaspirates are enriched with either freshly isolated SVF or ex vivo culture-expanded ADSCs^[51]. In this context, ADSCs function as “biologic factories”, secreting a potent cocktail of pro-angiogenic and immunomodulatory factors that mitigate early inflammatory insult and facilitate host-graft integration^[52]. The clinical applications of CAL have been increasingly explored. A landmark randomized controlled trial by Kølle et al. reported a remarkable 80.9% volume retention on day 121 with ADSC enrichment, compared to a mere 16.3% in controls [an absolute difference of 64.6 percentage points (pp)]^[53,54]. Although promising results have been reported, the clinical superiority of CAL over conventional fat grafting has not been consistently reproduced across all studies^[51]. Differences in cell preparation methods, enrichment strategies, and outcome assessment criteria may contribute to the observed variability. This distinction underscores the importance of cell potency and dosage, though the ADSCs still face stringent regulatory and logistical hurdles^[4,55-57].

Beyond volume, ADSCs are being instructed through innovative co-culture or functional enhancement strategies. For instance, co-culturing ADSCs with vascular regenerative cells (RE-01 cells) has been shown to achieve superior graft retention even with a tenfold reduction in cell dosage, signaling a shift toward precision cell therapy^[58]. Furthermore, the field is pivoting toward a cell-free protocol, utilizing ADSC-exos. These nanovesicles recapitulate the parent cell’s benefits while offering a superior safety profile, easier storage, and reduced risks of immunogenicity or unwanted differentiation^[59-61].

Managing recalcitrant wounds, such as DFUs and major burns, remains a formidable challenge where ADSCs offer significant therapeutic leverage^[62]. The pathophysiology of chronic wounds - often characterized by a stalled M1 inflammatory phase - is directly countered by the ADSCs’ ability to drive M2 macrophage polarization, thereby re-initiating the regenerative cascade^[47,63]. The key mechanism by which ADSCs promote the healing of DFUs is closely related to their powerful paracrine effect. Studies have shown that ADSC-exos are rich in various functional miRNAs, such as miR-451a, let-7c, miR-146, etc.^[63,64]. These miRNAs target key molecules such as macrophage migration inhibitory factor (MIF), interferon regulatory factor 1 (IRF1), and CCAAT/enhancer-binding protein delta (C/EBP-δ), and jointly regulate the polarization of macrophages to the M2 anti-inflammatory phenotype, thereby breaking the pathological state of the chronic wound where the M1 inflammatory phase is stagnant. This creates a favorable immune microenvironment for tissue regeneration. Additionally, the growth factors secreted by ADSCs activate signaling pathways, promoting the proliferation and migration of vascular endothelial cells, protecting fibroblasts from apoptosis and accelerating re-epithelialization and collagen deposition. Based on these mechanisms, to enhance the therapeutic efficacy of ADSC-exos, researchers have adopted various engineering strategies. Among them, hypoxic preconditioning has been proven to effectively enrich the functional miRNAs in exosomes, which target inflammatory-related genes and activate signaling pathways such as PI3K/AKT, jointly regulating the polarization of macrophages to the M2 type, promoting the proliferation and migration of fibroblasts, and enhancing the function of vascular endothelial cells, thereby accelerating wound healing through multiple targets^[46,47,61]. For deep-tissue defects, 3D-bioprinted hydrogel scaffolds co-delivering ADSCs and nitric oxide (NO) donors have demonstrated synergistic effects, promoting rapid re-epithelialization and organized collagen deposition^[52,65,66]. Despite these encouraging findings, the clinical evidence for ADSC-based treatment of chronic wounds remains less mature than the preclinical evidence. Most available studies are experimental or translational, with substantial variation in cell source, delivery strategy, wound models, and outcome assessment. Therefore, the reproducibility and clinical relevance of these findings remain to be established in adequately powered controlled clinical trials.

ADSCs are equally pivotal in modulating the late stages of tissue repair to prevent pathological scarring. Their anti-fibrotic efficacy is primarily mediated through the inhibition of TGF-β1/Smad signaling, which prevents the transition of fibroblasts into hyperactive myofibroblasts^[47]. Additionally, ADSCs help restore the ECM balance by upregulating MMPs while suppressing their inhibitors [tissue inhibitors of metalloproteinases (TIMPs)]^[67]. Clinical evidence, including a systematic review of 665 patients, suggests potential benefits of ADSCs or SVF in improving both the functional and aesthetic outcomes of scars^[68]. Emerging data highlight the role of ADSC-exos in alleviating the progression of various fibrotic diseases via mitochondrial restoration and targeted miRNA delivery^{[47,60,63,68]}. In aesthetic practice, the efficacy of local ADSC-exos or direct ADSC injection for acne scars has been confirmed to be comparable to that of fractional CO₂ laser treatment, indicating their potential as independent regenerative therapies. A randomized controlled study by Abou Eitta et al. demonstrated that a single ADSC injection was as effective as three sessions of fractional CO₂ laser in improving acne scars^[69]. Additionally, ADSC-exos can serve as an adjunct to fractional CO₂ laser treatment, significantly enhancing efficacy, reducing erythema, and shortening recovery time^[59]. These findings collectively support ADSCs and their exosomes as effective strategies for acne scar treatment, with their non-invasive and repeatable nature offering unique application value in aesthetic practice.

However, the strength of this evidence remains limited by heterogeneity in scar type, cell preparation, treatment protocols, comparator interventions, and outcome measures. Although some controlled studies suggest efficacy comparable to established treatments, the available evidence does not yet establish ADSC-based therapy as a standardized or superior treatment for scar management.

In the realm of aesthetic medicine, ADSCs have garnered attention for their ability to combat both intrinsic and extrinsic aging^[70,71]. By neutralizing reactive oxygen species (ROS) and stimulating resident dermal fibroblasts, ADSCs can increase dermal thickness and restore elastic fiber architecture^[72,73]. While clinical data suggest improvements in skin elasticity and hydration, meta-analyses have highlighted substantial heterogeneity in aesthetic outcomes, with some studies reporting limited or non-significant effects on wrinkle reduction^[70]. This variability may reflect differences in administration routes, treatment protocols, and patient characteristics. Nevertheless, high-dose intradermal ADSC injections have demonstrated sustained facial rejuvenation for over a year, potentially through the activation of underlying facial musculature via exosomal signaling^[73]. The use of ADSC-conditioned medium (ADSC-CM) also represents a growing trend, offering a potent, non-invasive secretome cocktail that protects against ultraviolet (UV)-induced senescence^[28].

The chondrogenic and osteogenic potential of ADSCs is being harnessed for complex craniofacial reconstruction^[74]. Most clinical applications involve combining ADSCs with osteoconductive scaffolds like β-tricalcium phosphate (β-TCP) for mandibular or cranial defects^[61]. In rhinoplasty, the convergence of ADSC biology and 3D bioprinting allows for the creation of patient-specific, stable cartilage constructs using bio-inks like gelatin methacryloyl (GelMA)^[75]. Innovative injectable systems using ADSC-incorporated microspheres now offer a minimally invasive alternative for minor nasal contouring, bypassing the morbidity associated with traditional rib cartilage harvesting^[76]. The evidence for craniofacial cartilage and bone regeneration remains predominantly preclinical or early translational. Outcomes are highly dependent on scaffold composition, cell source, differentiation conditions, and defect characteristics, which limits direct comparison between studies. Further long-term clinical studies are needed to determine the durability, safety, and functional relevance of these approaches.

A summary of key clinical studies on ADSCs in plastic surgery is provided in Table 1.

Despite the promising clinical outcomes, the lack of standardized protocols for ADSC isolation, expansion, and administration remains a primary bottleneck^[79]. The biological properties of ADSCs are significantly influenced by donor characteristics [e.g., body mass index (BMI), age, and anatomical harvest site] and processing techniques (enzymatic vs. mechanical)^[12,22]. To move toward large-scale clinical application, it is imperative to establish Good Manufacturing Practice (GMP) standards and universal characterization criteria^[80]. Furthermore, varying international regulatory classifications - ranging from minimally manipulated tissue to advanced therapy medicinal products - pose significant hurdles for global clinical translation and multicenter trials^[11,32]. At present, the lack of standardized separation protocols and the significant impact of donor characteristics on cell quality make it extremely difficult to establish a unified risk monitoring system. Therefore, future research should not be limited to the observation of short-term complications, but should focus on building an early warning model based on single-cell omics, to achieve a leap from empirical application to precise regenerative medicine.

A critical concern in plastic surgery, particularly in breast reconstruction following malignancy, is the potential for ADSCs to promote tumor recurrence or metastasis via their pro-angiogenic and anti-apoptotic signaling^[81]. While available clinical evidence has not demonstrated a clear increase in oncological risk associated with CAL, the pro-angiogenic secretome of ADSCs, including VEGF and hepatocyte growth factor (HGF), warrants continued vigilance in post-oncologic reconstruction, particularly given the potential for interactions with residual or dormant tumor cells^[82-84]. The powerful paracrine effect of ADSCs, through the secretion of VEGF, HGF and various cytokines, promotes the vascularization of transplanted fat but may also influence the local tumor microenvironment, highlighting the need for continued oncologic surveillance. In addition, the transcriptional heterogeneity of ADSCs further complicates risk assessment. Studies have shown that the drift of cell subpopulations during in vitro culture may increase the risk of embolism in the host^[79]. Rigorous, large-scale prospective randomized controlled trials with extended follow-up periods are essential to definitively establish the safety profile of ADSC-based therapies. Clinically, these potential risks support careful patient selection and individualized timing of CAL rather than a universal waiting period. CAL should preferably be considered after completion of oncological treatment and confirmation of no active disease, with the timing determined according to tumor characteristics and recurrence risk; an interval of approximately 6-12 months may be considered in selected post-radiotherapy patients^[85].

The future of ADSCs in plastic surgery lies at the intersection of bioengineering and molecular medicine. 3D Bioprinting technology enables the creation of customized, ADSC-laden scaffolds that mimic the complex architecture of craniofacial bones or soft tissue defects, offering a path toward precision reconstructive surgery^[86]. Simultaneously, the shift toward cell-free therapies using ADSC-derived exosomes represents a transformative trend^[87]. Exosome-based products may retain some of the regenerative properties associated with ADSCs while offering potential advantages in terms of stability, immunogenicity, and translational feasibility, potentially serving as biological agents for wound repair and aesthetic enhancements^[88]. Beyond these emerging strategies, further investigation is also warranted to clarify and optimize the potential applications of ADSCs in breast remodeling and reconstruction, facial soft-tissue restoration, and protection against UV-related skin damage and photoaging^[89]. Future studies should focus on improving the consistency, safety, and long-term efficacy of these approaches and on translating promising preclinical findings into well-controlled clinical applications.