From discarded tissues to therapeutic assets: Optimizing mesenchymal stem cell sources and secretome signatures for clinical translation

Abstract

Discarded biological tissues increasingly reveal unexpected value as regenerative reservoirs, particularly as sources of mesenchymal stem cells (MSCs) and their secretome-based therapeutic products. In the recent issue of World Journal of Stem Cells, Dam et al reinforce this paradigm by showing that MSCs derived from different adipose fractions share core phenotypic characteristics yet display source-dependent paracrine signatures - most notably in their differential growth factor profiles - that critically influence therapeutic behavior. From the perspective of oral and maxillofacial surgery, tissues routinely discarded during clinical procedures - including dental pulp, exfoliated deciduous teeth, periodontal ligament, and apical papilla - represent accessible and ethically favorable sources enriched with potent MSC populations. Owing to their neural crest origin, dental-derived MSCs exhibit unique proliferative dynamics and a distinct secretome composition, positioning them as strong candidates for next-generation cell-free regenerative strategies. Reframing these tissues as regenerative assets enables new opportunities for biobanking, mechanistic exploration, and precision engineering of MSC secretomes to improve therapeutic consistency. Progress in this direction will require harmonized isolation standards and systematic characterization of secretome heterogeneity to support the clinical translation of these unconventional yet highly valuable MSC reservoirs into deployable regenerative products.

Key Words: Oral stem cells; Regenerative medicine; Exosomes; Extracellular vesicles; Secretome; Mesenchymal stem cells

Core Tip: This editorial reframes discarded biological tissues, particularly those from oral and maxillofacial surgery, as valuable regenerative assets rather than medical waste. Drawing on comparative insights from adipose-derived mesenchymal stem cells, we highlight how the neural crest origin of dental mesenchymal stem cells endows them with unique secretome signatures and therapeutic potential. Furthermore, we discuss advanced engineering strategies - such as hypoxic preconditioning, three-dimensional culture, and smart hydrogel delivery - to overcome secretome heterogeneity and facilitate the clinical translation of these cell-free therapies for precision regenerative medicine.

This editorial refers to “Adipose-derived mesenchymal stem cells from solid tissue and lipoaspirates: A comparative study of phenotype, growth, and secretome” by Dam et al, 2026; https://doi.org/10.4252/wjsc.v18.i1.110470.

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INTRODUCTION

The field of regenerative medicine has long been dedicated to identifying mesenchymal stem cell (MSC) sources that are both easily accessible and possess robust differentiation and immunomodulatory potentials. Adipose tissue, due to its minimally invasive harvesting and abundant cell yield, has become a mainstream choice for clinical translation[1,2]. However, a recent comparative study by Dam et al[3] published in the World Journal of Stem Cells on adipose-derived MSCs (ASCs) has revealed that while ASCs from different harvesting sites share core phenotypes, their secretome signatures exhibit significant source-dependent differences. This finding not only emphasizes the decisive impact of tissue origin on therapeutic potential but also provides a critical theoretical pivot for re-examining biological tissues that are routinely discarded in clinical practice.

The comparative analysis by Dam et al[3] offers a pivotal lesson in source-dependent heterogeneity. The primary strength of their study lies in its rigorous paired design, which effectively minimized donor variability to reveal that MSC secretomes are strictly dictated by their tissue niche. While observing identical immunophenotypes across isolation methods, their detection of fibroblast growth factor-2 exclusively in lipoaspirates vs keratinocyte growth factor in solid tissue highlights a critical functional divergence. Their data demonstrate that even within the same tissue type, subtle differences in harvesting can produce clearly divergent secretome signatures - a degree of sensitivity that our current “MSC equivalence” assumptions fail to accommodate. However, a notable limitation of their work is that the scope was confined exclusively to mesoderm-derived adipose tissues. If such profound variability emerges within a single mesodermal lineage, it raises a more fundamental question: How much greater functional divergence should we expect when comparing MSCs with entirely different developmental origins? This limitation directly motivates a deeper examination of neural crest-derived MSCs from oral and maxillofacial tissues, whose developmental programming and paracrine profiles differ categorically from their adipose counterparts.

Indeed, emerging evidence supports this distinction. Recent large-scale comparative studies have confirmed that extracellular vesicles (EVs) derived from MSCs of diverse origins - including bone marrow, adipose tissue, and dental pulp - exhibit profound heterogeneity in cargo content, tissue affinity, and organ biodistribution[4]. In this context, the oral cavity represents a unique and underutilized frontier. Tissues routinely discarded as medical waste in oral and maxillofacial surgery - such as extracted deciduous teeth, dental pulp from wisdom teeth, and the apical papilla - constitute highly valuable regenerative assets. Unlike the mesoderm-derived cells discussed by Dam et al[3], these oral MSCs retain the unique imprinting of the cranial neural crest. This distinct embryonic origin confers them with superior neurogenic potential, as evidenced by their ability to inhibit neuroinflammation in subarachnoid hemorrhage[5] and promote neural maturation[6]. Furthermore, oral MSCs display unique immunomodulatory capabilities, effectively regulating macrophage polarization and regulatory T cell conversion in inflammatory environments[7,8], while also exerting profound effects on fibroblast-mediated soft tissue remodeling[9]. Consequently, we must shift our translational paradigm: Rather than seeking a generic cell source, we should leverage these specific waste tissues to develop precision therapeutic products by mapping their unique secretome signatures to matched clinical indications.

THE VALUE OF ORAL MSCS IN CLINICAL DISCARDED TISSUES

Traditional views often regard bone marrow as the “gold standard” source for MSCs[10]. However, research by Li et al[4] clearly indicates significant heterogeneity in EVs derived from MSCs of different tissue origins, a factor directly related to the precision of clinical applications. Unlike mesoderm-derived bone marrow or adipose MSCs, oral-derived MSCs [such as dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHED), and periodontal ligament stem cells (PDLSCs)] retain the high plasticity of neural crest cells.

This origin advantage endows them with unique biological behaviors. For instance, under hypoxic preconditioning, SHED can significantly upregulate hypoxia inducible factor-1 alpha, thereby enhancing angiogenic capacity through autocrine and paracrine mechanisms - a characteristic that offers irreplaceable advantages in the treatment of ischemic diseases[11]. More importantly, oral-derived MSCs possess inherent ethical advantages and low invasiveness in acquisition, as they are often derived from waste samples generated during routine extraction surgeries. Studies show that even DPSCs isolated from carious teeth, despite having slightly lower dopaminergic differentiation efficiency than those from healthy teeth, still retain basic neural differentiation potential, suggesting that even in pathological states, these tissues may still harbor therapeutic value[12]. Furthermore, stem cells from the apical papilla isolated from the root apex demonstrate excellent proliferation and differentiation capabilities when treated with novel endodontic materials, further confirming the core status of such tissues in regenerative endodontic therapy[13].

Therefore, we can establish a new resource perspective: Viewing every extraction surgery as an opportunity for cell banking or drug development. By establishing standardized biobanks and systematically collecting these discarded tissues, we can not only reserve autologous seed cells for individual patients but also provide abundant raw materials for the development of off-the-shelf cell-free therapies.

FUNCTIONAL DIFFERENCES IN ORAL MSC SECRETOMES AND EXOSOMES

In the context of oral and maxillofacial regeneration, this paradigm shift is particularly relevant because many functionally distinctive MSC secretomes originate from tissues that are routinely discarded during dental and maxillofacial procedures. With the rise of the cell-free therapy concept, the therapeutic focus of MSCs has gradually shifted from cell replacement to paracrine effects, particularly the functions of EVs like exosomes. The aforementioned ASC research highlighted differences in growth factor secretion from cells derived from different adipose fractions, and this pattern is equally applicable and even more complex in oral MSCs.

Recent literature indicates that EVs from different tissue sources show significant differences in cargo diversity, cell affinity, and organ biodistribution[4]. For example, DPSC-derived exosomes, when treating spinal cord injury, can specifically inhibit M1 macrophage polarization via the reactive oxygen species (ROS)-mitogen-activated protein kinases-nuclear factor kappa B pathway, an anti-inflammatory efficacy closely related to their specific microRNA (miRNA) cargo[14]. In rheumatoid arthritis models, EVs derived from gingival MSCs precisely regulate the regulatory T/T helper type 17 immune balance by carrying miR-148a-3p, demonstrating strong immune targeting[15].

This heterogeneity presents both a challenge and an opportunity. The challenge lies in the high product consistency required for clinical translation, while the opportunity lies in our ability to customize cell sources according to disease requirements. For instance, for neurological disorders (e.g., traumatic brain injury), EVs derived from SHED are rich in neuroprotective factors like miR-330-5p, effectively regulating microglia polarization and promoting motor function recovery[16]; whereas for periodontal bone defects, EVs secreted by DPSCs show stronger osteoinductive ability, especially when carrying miR-378a, which significantly promotes local angiogenesis via the Hedgehog/Gli1 pathway[17].

Furthermore, secretome efficacy is not static but highly dependent on microenvironmental conditioning. Aging is a major bottleneck limiting MSC application, but research by Shi et al[18] found that EVs derived from gingival MSCs can significantly alleviate oxidative stress-induced senescence in endothelial cells and fibroblasts, exerting a rejuvenation effect by inhibiting the mammalian target of rapamycin signaling pathway. Even more intriguingly, SHED-derived exosomes from young donors can reverse functional decline in aged tendon stem cells, suggesting that this intergenerational information transfer offers new insights for anti-aging therapies[19]. To more intuitively demonstrate the unique value of these discarded tissues as therapeutic assets, we summarize the key secretome characteristics and potential clinical applications of different oral MSC sources in Table 1[11-37].

Table 1 Mechanisms and therapeutic applications of oral mesenchymal stem cell-derived secretomes.

Source	Key mechanism	Therapeutic application	Ref.
GMSCs	Matrix-bound vesicles on 3D microchannels	Reducing stenosis in tracheal regeneration	[20]
GMSCs	Inhibition of mTOR signaling pathway	Anti-aging for skin and vasculature	[18]
GMSCs	miR-148a-3p regulation of Treg/Th17 balance	Precision therapy for rheumatoid arthritis	[15]
GMSCs	Optimized xeno-free culture conditions	High-yield and safe secretome production	[21]
DPSCs	Scalable expansion in hollow fiber bioreactors	Standardized extracellular vesicle manufacturing	[22]
DPSCs	Restoration of tight junction protein expression	Treating aging-related salivary hypofunction	[23]
DPSCs	Inhibition of ROS-MAPK-NF-κB pathway	Anti-inflammation in spinal cord injury	[14]
DPSCs	Osteoinductive EVs in HA/PEG hydrogels	Bone defect repair and mineralization	[24]
DPSCs	Distinct proteomic profiles in 3D spheroids	Culture-dependent osteogenic enhancement	[25]
DPSCs	Hypoxic miR-210-3p targeting NF-κB p105	Alleviating inflammatory osteolysis	[26]
DPSCs	Biomimetic aggregates with decellularized matrix	Whole tooth regeneration	[27]
DPSCs	Antioxidant enzyme induction by senescent EVs	Adaptive response to oxidative stress	[28]
DPSCs	Secretion from carious tissue-derived cells	Dopaminergic neural differentiation	[12]
SHED	Biglycan delivery via youthful sEVs	Rejuvenating aged periodontal bone	[29]
DPSCs	Exosome delivery via HA-vinyl sulfone hydrogels	Protecting subchondral bone in TMJ osteoarthritis	[30]
SHED	miR-330-5p mediated M2 microglia polarization	Motor recovery in traumatic brain injury	[16]
SHED	miR-24-3p targeting IL-1R1/p-p38 MAPK	Alleviating trigeminal neuralgia	[31]
SHED	HIF-1α stabilization and VEGF upregulation	Enhancing angiogenesis in tissue engineering	[11]
SHED	Hypoxic exosomes on bioinspired microspheres	Vascularized bone regeneration	[32]
SHED	miR-1246 activation of macrophage autophagy	Wound healing with itch relief	[33]
SHED	Modulation of histone methylation and NF-κB	Reversing tendon stem cell senescence	[19]
DPSCs	miR-378a targeting Sufu/Hedgehog pathway	Local angiogenesis in inflammatory environments	[17]
PDLSCs	Mechanical force-induced ANXA3 enrichment	Regulating orthodontic bone remodeling	[34]
PDLSCs	Healthy exosome regulation of Wnt signaling	Rescuing osteogenesis in periodontitis	[35]
SCAP	Conditioning with bioceramic iRoot FM	Proliferation under inflammation	[13]
SCAP	Ultrasound-induced sphingomyelinase upregulation	Enhancing EV yield and bioactivity	[36]
DFSCs	ROS-responsive hydrogel delivery system	On-demand antioxidation for pulpitis	[37]

GMSCs: Gingival mesenchymal stem cells; DPSCs: Dental pulp stem cells; SHED: Stem cells from human exfoliated deciduous teeth; PDLSCs: Periodontal ligament stem cells; SCAP: Stem cells from the apical papilla; DFSCs: Dental follicle stem cells; 3D: Three-dimensional; mTOR: Mammalian target of rapamycin; Treg: Regulatory T; Th17: T helper type 17; ROS: Reactive oxygen species; MAPK: Mitogen-activated protein kinases; NF-κB: Nuclear factor kappa B; EVs: Extracellular vesicles; HA: Hyaluronic acid; PEG: Poly ethylene glycol; sEVs: Small extracellular vesicles; IL-1R1: Interleukin-1 receptor type 1; HIF-1α: Hypoxia inducible factor-1 alpha; VEGF: Vascular endothelial growth factor; ANXA3: Annexin A3.

ENGINEERING STRATEGIES TO ENHANCE MSC SECRETOME EFFICACY

To transform these laboratory assets into clinically usable products, engineering approaches must be employed to overcome the heterogeneity and instability of the natural secretome. Current strategies focus primarily on two dimensions: Preconditioning and delivery systems.

Preconditioning strategies to improve secretion efficacy

To maximize the utility of limited biological waste materials, simulating physiological microenvironments is essential for boosting secretome yield. Hypoxic preconditioning, for instance, is a prime example demonstrated by Tian et al[26], who confirmed that hypoxic culture not only increased the EV yield from dental pulp tissue but, more importantly, enriched miR-210-3p. This allowed the EVs to inhibit osteoclastogenesis while promoting M2 macrophage polarization, thereby effectively treating inflammatory osteolysis[26]. Additionally, treating stem cells from the apical papilla with physical stimuli such as low-intensity pulsed ultrasound has been proven to significantly increase EV secretion by upregulating neutral sphingomyelinase and to enhance their osteogenic and anti-inflammatory activities[36]. Mechanical force stimulation can even alter the proteomic profile of PDLSC exosomes, enriching key proteins like annexin A3, thus playing a critical role in regulating bone metabolism during orthodontic tooth movement[34].

Three-dimensional culture and biomimetic microenvironments

Traditional two-dimensional (2D) culture often leads to loss of MSC stemness, whereas three-dimensional culture systems better mimic the in vivo microenvironment. Liu et al[20] developed a perfusable microchannel scaffold combined with GMSC-derived vesicles, successfully modulating the immune microenvironment of tracheal substitutes and drastically reducing the incidence of granuloma-related stenosis. Proteomic analysis by Raik et al[25] also indicated significant differences between the secretomes of DPSCs cultured as three-dimensional spheroids vs 2D monolayers. Under specific conditions, the 2D secretome performed better in cranial defect repair, suggesting the need to select culture modes based on specific regeneration goals (e.g., osteogenesis vs vascularization)[25]. Furthermore, a biomimetic tooth bud microenvironment constructed using decellularized tooth matrix and stem cell aggregates has been confirmed to achieve functional tooth regeneration in large animal models and even clinical pilot studies via exosome-mediated mechanisms[27].

Smart delivery systems for exosomes

Rapid clearance remains a bottleneck that compromises the efficiency of waste-derived therapeutic products. To preserve these assets, functionalized hydrogels are employed as sustained-release carriers. For example, the hyaluronic acid/poly ethylene glycol hydrogel system developed by Wang et al[24] achieved sustained release of dental pulp stem cell-derived EVs, significantly promoting bone defect repair. Diez-Guardia et al[30] used hyaluronic acid-vinyl sulfone hydrogels to load DPSC-derived exosomes for treating temporomandibular joint osteoarthritis, confirming the advantages of sustained-release systems in maintaining subchondral bone integrity. More innovatively, light-responsive or ROS-responsive hydrogels (such as the SA-RhB hydrogel designed by Li et al[37]) can intelligently release EVs based on ROS levels in the inflammatory microenvironment, achieving on-demand delivery and precise anti-inflammation.

Key challenges facing clinical translation

Although oral-derived MSCs and their secretomes have shown exciting prospects in animal models, the path to the clinic still faces severe challenges. The primary hurdle is the inconsistency of the raw material. Unlike standardized cell lines, the quality of these “biological waste” samples is highly unpredictable, depending heavily on factors like donor aging or local inflammation, which Li et al[4] noted as a major barrier to clinical translation. Therefore, strict Chemistry, Manufacturing, and Controls protocols are mandatory. We need to establish full-process standards covering cell isolation, culture conditions (e.g., serum-free, xeno-free culture[21]), EV enrichment methods (ultracentrifugation vs tangential flow filtration), and potency assay testing. Pincela Lins et al[22] attempt to scale up DPSC-EV production in hollow-fiber bioreactors provides a vital reference for solving manufacturing scalability issues. The second challenge is the deep elucidation of mechanisms. While we know that miRNAs (such as miR-24-3p[31], miR-1246[33]) and specific proteins play key roles in therapy, the secretome is a complex cocktail system. Future research needs to combine single-cell sequencing and multi-omics technologies to map the dynamic changes of MSC secretomes under different pathological states (e.g., periodontitis[17,35], aging[23,28]) to realize mechanism-based precision therapy. For instance, using exosomes from healthy PDLSCs to rescue the osteogenic capacity of inflammation-damaged stem cells in periodontitis-induced bone loss represents a mechanism-based precision repair strategy[29,35].

Finally, safety and ethical considerations must be addressed. Although cell-free therapy avoids the tumorigenic risks of live cell transplantation, exosomes act as bioactive carriers, and their long-term safety still requires full verification in large animal models. Particularly in applications involving immune modulation, such as treating rheumatoid arthritis[15] or spinal cord injury[14], vigilance against potential immunosuppressive side effects is necessary.

CONCLUSION

Extracting therapeutic assets from clinically discarded oral and maxillofacial tissues, such as teeth and periodontal ligaments, represents an emerging and conceptually important direction in regenerative medicine. This strategy not only turns waste into treasure but also, through cell-free exosome carriers, ingeniously circumvents many barriers of traditional cell therapy. Comparative studies on ASCs provide an important reference framework, while oral and maxillofacial MSCs, characterized by their neural crest origin, are increasingly recognized for their distinct biological properties[38-40]. In the future, by integrating biomaterials engineering, microenvironmental preconditioning, and high-throughput omics analysis, we hope to transform these discarded tissues into standardized, off-the-shelf regenerative medicines, bringing significant progress to trauma repair, inflammation control, and anti-aging therapies (Figure 1).

Figure 1 Schematic illustration of the translational strategy to transform discarded tissues into therapeutic assets. The figure was created with Figdraw. MSCs: Mesenchymal stem cells; ED: Exfoliated deciduous teeth; PDL: Periodontal ligament; AP: Apical papilla.