Regenerative medicine has emerged as a transformative discipline aiming to restore, replace, or regenerate damaged tissues and organs through the integration of cellular, molecular, and bioengineering approaches1,2. Mesenchymal stem cells (MSCs) have garnered widespread attention as powerful biological tools due to their capacity for self-renewal, multilineage differentiation, and robust paracrine secretory activity3,4,5. The therapeutic action of MSCs was historically attributed to their ability to engraft, differentiate, and substitute for damaged cells6,7. An overview of the major components of the MSC secretome is presented in Figure 1. However, a growing body of evidence over the past decade indicates that most of their therapeutic effects are exerted indirectly via the release of soluble factors, such as cytokines, growth factors, extracellular vesicles, and, more recently, bioactive peptides8.

MSC-derived peptides (MSC-DPs) represent a unique and biologically active component of the MSC secretome; they comprise small amino acid sequences with diverse biological activities9,10. These peptides enhance tissue repair by modulating inflammation, oxidative stress, apoptosis, angiogenesis, and metabolism11,12. Due to their small size, they can penetrate tissues effectively; furthermore, they are stable in the extracellular environment, and their immunogenicity is significantly lower than that of full-length proteins or intact cells. Most importantly, they offer a cell-free therapeutic alternative that overcomes the limitations associated with live-cell transplantation, including low survival rates, potential tumorigenicity, and ethical or regulatory constraints13,14.

Both human and xenogenic MSCs secrete a complex secretome composed of cytokines, growth factors, extracellular vesicles, and bioactive peptides. Among these, MSC-DPs act as core paracrine mediators of regeneration, promoting angiogenesis, immunomodulation, antioxidation, and metabolic regulation across species (cf. Figure 2). Expanding beyond human-derived MSC-DPs, emerging evidence indicates that xenogenic MSCs—particularly those derived from ovine, porcine, and bovine tissues—represent promising alternative reservoirs of bioactive peptides with comparable immunomodulatory and regenerative capacities15. Studies on equine MSCs have confirmed the secretion of antimicrobial and pro-regenerative peptides with significant therapeutic activity across species boundaries16. Similarly, bovine and porcine MSCs have been characterized as rich peptide sources supporting tissue repair and translational research17,18.

Evidence also demonstrates that xenogenic MSCs and their secreted factors can modulate immune responses across species, as observed in feline and canine models treated with xenogeneic MSC secretomes and cells19,20,21. Ovine umbilical cord MSCs have likewise been established as stable, immortalized sources suitable for scalable peptide isolation and comparative xenogenic studies22. These MSC-DPs demonstrate bioactivity equivalent to their human counterparts, with some exhibiting anti-inflammatory23, angiogenic24, and antioxidative activities across species25. Further evidence reinforces that xenogenic MSCs and their secreted factors can modulate the immune system across species, highlighting the translational potential of such peptides for preclinical and veterinary applications26,27. However, interspecies molecular compatibility, immunogenic epitopes, and peptide stability remain critical challenges requiring systematic research prior to clinical application28,29.

The isolation of MSC-DPs has been facilitated by advances in proteomics and peptidomics, particularly high-resolution mass spectrometry and bioinformatics-based peptide mapping. These technologies have enabled the identification of numerous peptides originating from MSC cytosolic proteins, membrane components, and extracellular matrix modulators30,31,32. Functionally, they replicate most of the classical MSC functions, such as promoting angiogenesis via vascular endothelial growth factor (VEGF)-like sequences or dampening inflammation through interleukin-10 (IL-10)–mimetic domains, thereby enhancing the treatment repertoire of MSC-based therapies33,34. Cell-to-peptide regenerative approaches bridge the translational gap in the emerging shift towards next-generation biologics with enhanced safety, scalability, and molecular accuracy35,36. MSC-DPs constitute a standardized, reproducible, and ethically sound therapeutic platform applicable across a wide range of pathological conditions, including cardiovascular, neurodegenerative, musculoskeletal, and metabolic disorders37.

This review aims to comprehensively address the biological origin, mechanism of action, and therapeutic potential of MSC-DPs. Emphasis is placed on their molecular mechanisms—ranging from paracrine signaling and immunomodulation to angiogenic and metabolic regulation—as well as their synergistic effects when combined with organ-specific peptides. Moreover, the discussion includes the relative advantages of peptide therapy over traditional cell therapy, existing limitations in peptide stability and delivery, and future prospects for clinical translation. Having outlined the scope of this review, the subsequent section explores the biological origin and composition of MSC-DPs, which form the basis of their functional properties.

A comprehensive literature search was conducted to identify relevant studies elucidating the biological and therapeutic roles of mesenchymal stem cell–derived peptides (MSC-DPs). Multiple electronic databases, including PubMed, Scopus, and Web of Science, were systematically searched for peer-reviewed articles. The search strategy utilized varied combinations of keywords, such as “mesenchymal stem cells,” “MSC secretome,” “MSC-derived peptides,” “peptidome,” “extracellular vesicles,” “regenerative medicine,” and “cell-free therapy”. The literature search primarily focused on publications spanning the period from 2010 to 2025, although earlier seminal studies were included where contextually relevant. Only articles published in English that were directly pertinent to the topic were considered for inclusion. Both experimental and review studies were included to provide a comprehensive overview; conversely, studies lacking sufficient methodological clarity or direct relevance to MSC-derived peptides were excluded.

MSC-DPs originate from multiple intracellular and secretory compartments, collectively reflecting the dynamic proteolytic, metabolic, and paracrine activities of mesenchymal stromal cells38,39. Their structural diversity arises from regulated protein turnover, enzymatic cleavage of membrane structures, and active secretion into the extracellular space. These peptide subsets contribute to the multifunctional therapeutic actions attributed to the MSC secretome and constitute a core component of cell-free regenerative strategies40,41.

Cytosolic peptides are generated primarily through proteasomal degradation, autophagy-associated processing, and intracellular stress–response pathways42,43. They frequently contain cysteine-, glycine-, or proline-rich motifs that enhance peptide stability and support antioxidant activity. These peptides participate in redox regulation, mitochondrial homeostasis, and protection against apoptosis, particularly under inflammatory or oxidative microenvironmental stress44. Their biochemical signatures reflect the adaptive metabolic responses of MSCs and contribute to the cytoprotective, anti-inflammatory, and survival-enhancing properties observed in MSC-DP therapy45,46.

Membrane-associated peptides originate from transmembrane receptors, adhesion molecules, and extracellular domain-bearing proteins that undergo controlled enzymatic cleavage or ectodomain shedding47. These peptides retain functional ligand-binding or receptor-interactive sequences, enabling them to modulate immune cell recruitment, extracellular matrix remodeling, and intercellular signaling48. By influencing integrin activity, chemokine responsiveness, and stromal–immune interactions, membrane-derived peptides help shape the regenerative microenvironment and amplify MSC-driven paracrine mechanisms49.

Extracellular peptides represent the actively released fraction of the MSC secretome and include angiogenic, immunoregulatory, cytoprotective, and metabolic-regulating sequences50. These peptides are released via exocytosis, extracellular vesicle secretion, and non-vesicular paracrine pathways. Subsequently, they act directly on target tissues to modulate inflammation, stimulate angiogenesis, enhance metabolic recovery, and promote structural repair. Their demonstrated activity in xenogenic models highlights their evolutionary conservation and therapeutic potential across species51,52. A consolidated overview of representative MSC-DP classes, properties, and bioactivities is presented in Table 1.

MSC-DPs execute their regenerative functions through multiple interconnected biological pathways that collectively reproduce many of the therapeutic effects typically attributed to mesenchymal stem cells67,68. A unifying feature of these mechanisms is their paracrine mode of action, whereby peptides—either freely secreted or packaged within extracellular vesicles—bind to receptors on neighboring cells and activate intracellular signaling cascades, such as PI3K/Akt, MAPK/ERK, and JAK/STAT69,70,71. Through these pathways, MSC-DPs promote fibroblast proliferation, endothelial migration, epithelial repair, and cellular survival under stress conditions, thereby establishing a pro-regenerative microenvironment that is independent of MSC engraftment72,73.

In this context, “mimetic” peptides refer primarily to endogenous low-molecular-weight peptides derived from the MSC secretome that exhibit functional similarity to established growth factors or cytokines, rather than to full-length proteins30,31,60. These must be clearly distinguished from synthetic or bioengineered analogs, which replicate similar biological activities but do not strictly fall within the definition of MSC-derived peptides. Specific peptide motifs contribute to these effects; for example, endogenous VEGF-mimetic peptide sequences stimulate endothelial tube formation, while IGF-like domains enhance cell survival under oxidative or inflammatory conditions74,75. Collectively, MSC-DPs exert immunomodulatory, antioxidative, angiogenic, and metabolic regulatory effects76,77, reflecting their role as key molecular mediators that translate the complex paracrine signals of MSCs into concise biochemical cues69.

The biological relevance of MSC-DPs is supported by a growing body of in vitro, in vivo, and preclinical evidence demonstrating their regenerative, immunomodulatory, and cytoprotective properties71. Cumulatively, these studies indicate that MSC-DPs replicate the majority of the therapeutic functions of intact MSCs, but with improved safety, reproducibility, and scalability93.

Notably, a significant proportion of current experimental and preclinical evidence is derived from studies employing the whole MSC secretome, conditioned media, or extracellular vesicle-associated formulations rather than purified MSC-derived peptides (MSC-DPs). Given the compositional complexity of the secretome, the therapeutic effects observed in these studies cannot be attributed solely to peptides, but are more likely the result of synergistic interactions among multiple bioactive components. Accordingly, such findings should be interpreted with caution when considered as direct evidence of MSC-DP efficacy.

The therapeutic efficacy of MSC-DPs can be significantly enhanced by coupling them with organ-specific or tissue-targeting peptides that direct their biological functions to precise cellular niches121. This synergy exploits the pleiotropic signaling of MSC-DP-mediated angiogenic, immunomodulatory, and antioxidative functions, coupled with the specificity and selectivity of organ-specific sequences, thereby creating multifunctional therapeutic platforms with immense potential for tissue-specific repair and systemic regulation122.

MSC-DPs, whether released in a soluble form or packaged within the secretome/EVs, represent a paradigm shift in regenerative medicine, designed to overcome the primary limitations associated with whole-cell transplantation38. Unlike living MSCs, which are encumbered by hurdles such as batch variability, low engraftment efficiency, senescence, and potential tumorigenesis, MSC-DPs offer distinct benefits; these include reduced immunogenicity, increased consistency, and the capacity for large-scale production under standardized conditions136.

Given that their active components are predominantly peptides, these therapeutics demonstrate efficient diffusion across extracellular matrices, facilitating rapid local pharmacodynamic effects at the site of injury137. Furthermore, as non-cellular bioproducts, peptide-rich MSC-DPs exhibit superior storage and distribution properties; they can be safely sterilized, lyophilized, and stored for extended periods with a highly stable shelf life under controlled conditions138. Consequently, these cell-free, peptide-rich formulations mitigate logistical concerns related to cell harvesting, expansion, and cryopreservation, ultimately rendering this form of regenerative medicine safer and more universally applicable139.

Beyond manufacturing advantages, MSC-DPs enable the precise regulation of regenerative mechanisms. Specifically, these bioactive components can selectively modulate angiogenesis, immune responses, oxidative balance, and metabolic pathways, thereby yielding more predictable and controllable outcomes compared to heterogeneous cell populations94. Pharmacologically, the structured and quantifiable composition of peptide-enriched secretome preparations facilitates standardized pharmacokinetic and pharmacodynamic assessments, thereby ensuring a more consistent dose–response relationship across batches140.

From an application standpoint, peptide-enriched cell-free formulations can be seamlessly integrated with biomaterial scaffolds, nanoscale delivery systems, or combined with small-molecule therapeutics, significantly enhancing their therapeutic versatility while maintaining high target specificity141.

In summary, MSC-DPs and peptide-enriched secretomes represent a straightforward, scalable, and ethically favorable platform that bridges the gap between complex cell-based therapies and conventional protein drugs142. By combining the biological sophistication of multicellular communication with the precision of molecular therapeutics, they truly embody the next generation of regenerative medicine.

Despite their therapeutic promise, MSC-DPs—whether free or secretome/EV-associated—still face several scientific and translational barriers hindering their widespread application in a clinical context143. Currently, the most significant challenge complicating MSC-DP development is inherent peptide variability, driven by differences in starting cell characteristics, tissue and species origin, and cell culture conditions; this variability poses a major hurdle for reproducibility and complicates comparative analyses across studies. Furthermore, standardized preparation and purification techniques for MSC-DPs remain underdeveloped; different cell culture, processing, and analytical methodologies—including proteolysis, chromatography, and mass spectrometry quantification—yield highly variable peptide signatures, thereby impeding the development of MSC-DPs in compliance with FDA Good Manufacturing Practice (GMP) standards144.

Additionally, from a pharmacological perspective, rapid enzymatic turnover and renal clearance compromise the in vivo half-life of these peptides, requiring advanced formulations—such as nanoparticle encapsulation, hydrogel embedding, or PEGylation—to extend peptide availability145. Another major concern for the development of MSC-DPs is immunogenicity; although less immunogenic than whole-cell-derived products, the potential for immune reactions remains significant for xenogeneic-derived peptides, necessitating comprehensive immune toxicity studies to ensure safety prior to clinical application146. Moreover, although xenogeneic peptides are generally less immunogenic than full-length proteins, cross-species administration may still induce immune responses, particularly following repeated exposure. Regulatory agencies, such as the U.S. Food and Drug Administration and the European Medicines Agency, require the rigorous evaluation of immunogenicity, safety, and long-term effects, while challenges related to batch consistency and source traceability further complicate clinical translation147,148. Furthermore, ambiguous regulatory definitions distinguishing natural MSC-DPs from synthetic peptides may complicate intellectual property protection, requiring harmonized global frameworks for widespread therapeutic application149.

An additional key limitation is the frequent extrapolation of therapeutic outcomes from whole secretome or conditioned media studies directly to MSC-derived peptides. Given the compositional complexity of the secretome, the precise therapeutic contribution of low-molecular-weight peptides remains insufficiently resolved. Future studies must prioritize the isolation, characterization, and functional validation of defined peptide sequences to establish clear structure–function relationships and enable the accurate assessment of their independent therapeutic potential150.

Overcoming these obstacles will require the interdisciplinary integration of bioengineering, computational biology, and translational medicine to improve the development pipeline for MSC-DPs151. Future directions will rely on the development of standardized platforms for peptide identification, ensuring reproducible peptide signatures across cellular origins, in conjunction with advanced, bioinformatics-driven models for predicting peptide sequences with potential biological functions152. In this respect, the integration of synthetic biology and peptide engineering may provide insights for designing novel, "hybrid" peptides with improved stability, targeted delivery, and precisely controlled potency153. Simultaneously, the further development of biomaterial-based delivery formulations, including "intelligent" hydrogels or exosome-mimetic vesicles, could provide a robust paradigm for overcoming pharmacokinetic hurdles and improving in vivo dwell time154,155,156.

Ultimately, a concerted effort between bench researchers, practicing clinicians, and regulatory experts is imperative to successfully translate emerging MSC-derived peptides into standardized, approved biologics with predictable safety, efficacy, and potency across various regenerative therapies (cf. Figure 5).

MSC-DPs are increasingly recognized as specialized mediators of MSC paracrine activity, offering a more defined and potentially scalable alternative to whole-cell therapy. Evidence from peptidomic profiling and early functional studies suggests that these peptides modulate several key regenerative pathways, including immune modulation, oxidative stress regulation, metabolic support, and tissue remodeling. Their small size, ease of synthesis, and potential for standardized formulation position them as highly promising candidates for next-generation, cell-free therapeutics.

Despite these advantages, research into MSC-DPs remains in its formative stages. Current findings are largely derived from heterogeneous experimental models, diverse MSC sources, and inconsistent culture or peptide-isolation protocols. These methodological differences limit direct comparisons across studies and generate uncertainty regarding the reproducibility of the reported peptide functions. Moreover, the mechanisms linking peptide sequences to specific biological effects remain poorly defined, while ongoing challenges related to peptide stability, targeted delivery, and in vivo persistence continue to hinder translational advancement.

In order to advance MSC-DPs toward clinical relevance, future research must prioritize standardized peptide-identification workflows, robust functional validation, and the development of delivery systems that enhance peptide stability and bioavailability. The integration of high-resolution proteomics, computational modeling, and biomaterial-based platforms will be critical in defining consistent peptide signatures and clarifying their mechanistic contributions.

Overall, MSC-DPs represent a promising, yet emerging, domain in regenerative medicine, requiring sustained and rigorous investigation before their therapeutic potential can be fully realized. Crucially, the definitive clinical validation of purified MSC-derived peptides remains lacking, further underscoring the need for rigorously designed, peptide-specific translational studies.

AMPK: AMP-activated protein kinase; BBB: Blood-brain barrier; BMP-2: Bone morphogenetic protein-2; COMP: Cartilage oligomeric matrix protein; ECM: Extracellular matrix; ERK: Extracellular signal-regulated kinase; EVs: Extracellular vesicles; FDA: Food and Drug Administration; FGF: Fibroblast growth factor; FGFR1: Fibroblast growth factor receptor 1; IFN-γ: Interferon gamma; IL-10: Interleukin-10; JAK/STAT: Janus kinase/Signal transducer and activator of transcription; MAPK: Mitogen-activated protein kinase; MMP: Matrix metalloproteinase; MSC: Mesenchymal stem cell; MSC-DPs: Mesenchymal stem cell-derived peptides; PDGF: Platelet-derived growth factor; PD-L1: Programmed death-ligand 1; PI3K/Akt: Phosphoinositide 3-kinase/Protein kinase B; RGD: Arginyl-Glycyl-Aspartic acid; ROS: Reactive oxygen species; RVG: Rabies virus glycoprotein; SCI: Spinal cord injury; SOD: Superoxide dismutase; TGF-β: Transforming growth factor beta; TIMP: Tissue inhibitor of metalloproteinases; TNF-α: Tumor necrosis factor alpha; VEGF: Vascular endothelial growth factor; VEGFR2: Vascular endothelial growth factor receptor 2

The authors would like to thank the OXYZ Health & Wellness Academy for their administrative and technical support during the preparation of this manuscript.

All authors contributed equally to the conception and design of the study. All authors read and approved the final manuscript.

This research was fully supported by OXYZ Health & Wellness Academy (Research and Development Department, Malaysia) as part of its ongoing scientific initiative on mesenchymal stem cell–based regenerative medicine and peptide integration studies.

No new data was generated for this review article. Data and materials used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Not applicable.

Not applicable.

The authors declare that they have not used generative AI (a type of artificial intelligence technology that can produce various types of content including text, imagery, audio and synthetic data).

The authors declare that they have no competing interests.