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Open research questions in Mesenchymal stem cell research

60 unresolved questions extracted from the limitations and future-work sections of 406 Mesenchymal stem cell research papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Although AD-MSCs demonstrate promising properties in wound healing, their use remains experimental due to donor heterogeneity, insufficient data safety and underlying mechanisms of action.

    Adipose tissue for reconstruction and wound healing: applications, challenges, and future directions · 2026 · DOI

  • Available evidence is dominated by short-duration phase 1/2 trials, with limited information on the safety of repeated MSC administration in routine practice.

    Real-world safety profile of repeated outpatient autologous adipose-derived mesenchymal stromal cell therapy: a single-center registry of 2,212 administrations with 553.5 person-years of follow-up · 2026 · DOI

  • Mesenchymal defects contribute to thymic abnormalities in congenital syndromes such as DiGeorge syndrome (DGS), CHARGE syndrome, and Trisomy 21 (T21), yet human studies are limited by the rarity of these conditions and restricted access to thymic tissue.

    Derivation of Mesenchymal Stem Cells from Induced Pluripotent Stem Cells and Their Application in Genetic Disease Modeling 2307485 · 2026 · DOI

  • These findings support further investigation of eMSC-EV-enriched preparations as a cell-free strategy for improving tissue remodeling in fibrotic skin conditions.

    Regenerative potential of extracellular vesicles from endometrial mesenchymal stem cells for modulating fibrosis and wound healing · 2026 · DOI

  • Extracellular vesicle-enriched preparations derived from human endometrial mesenchymal stem cells (eMSC-EV-enriched preparations) may possess regenerative and anti-fibrotic potential, yet their roles in scar modulation and underlying mechanisms remain unclear.

    Regenerative potential of extracellular vesicles from endometrial mesenchymal stem cells for modulating fibrosis and wound healing · 2026 · DOI

  • These findings suggest that cannabinoid-based preconditioning of UC-hMSC involves the HIF-1/VEGF axis and VEGFR-2/ERK signaling pathways in endothelial cells, supporting further investigation of this approach in wound healing and regenerative therapies.

    Purified CBD and CBD-rich full-spectrum Cannabis sativa extract potentiate the angiogenic paracrine function of umbilical cord derived mesenchymal stem cells · 2026 · DOI

  • Nevertheless, although extensive preclinical and clinical data support the safety of RRV-based suicide gene therapy, further evaluation of the interactions between MSC-ad/RRV and normal cells or tissues may provide additional mechanistic insights and warrants investigation in future studies.

    Mesenchymal stem cell-mediated delivery boosts the efficacy of suicide gene therapy based on retroviral replicating vectors in peritoneally disseminated cancer · 2026 · DOI

  • While these findings support further investigation of HP as a strategy to optimize stem cell-based therapy, the 4-hour observation window and associational nature of the 1 3Molecular Biology Reports (2026) 53:792 792 Page 10 of 11 data warrant caution when assessing clinical potential.

    Hypoxia-preconditioned bone marrow mesenchymal stem cells alleviate acute liver failure in association with the VEGF/c-Met pathway · 2026 · DOI

  • Although existing reviews have explored the role of MSCs or mitochondrial function in CIRI, few studies have systematically integrated the bidirectional regulatory relationship between dynamic mitochondrial function and immune network remodeling.

    A new perspective on mesenchymal stem cells and their derivatives in alleviating cerebral ischemia-reperfusion injury dynamically regulating mitochondrial function to remodel the immune network · 2026 · DOI

  • A promising direction appears to be the development of combined cell-based drugs that combine MSCs with M2-polarized macrophages; however, data on their clinical effectiveness are still insufficient.

    Cellular Products with Anti-Inflammatory Properties for the Treatment of Cartilage Lesions · 2026 · DOI

  • Prior study indicates that AD-SVF Exo can enhance human dental pulp stem cell (hDPSC) migration and proliferation, particularly at low concentrations, but their detailed time- and dose-dependent proliferative effects remain unclear.

    Time and Dose Dependent Effects of Adipose-Derived Stromal Vascular Fraction Exosomes on Human Dental Pulp Stem Cell Proliferation · 2026 · DOI

  • Precision medicine and patient-specific therapy Precision medicine can enhance SCT by matching personal biological traits with the most appropriate regenerative methods. The number of stem cells, lesion vascularity, and underlying etiologies may vary and affect therapeutic responses; however, existing staging systems do not fully consider these differences (63). Advanced imaging and molecular profiling can identify biomarkers to predict which patients are most likely to respond to marrow- or adipose-derived cell therapies, thereby enabling more selective clinical decisions (64). As awareness of disease heterogeneity increases, patient stratification may be part of treatment planning. Hereditary and epigenetic factors can help predict the likelihood of successful joint-saving interventions or their failure rates. The application of these tools in clinical care would help shift the treatment process toward personalized management and maximize regenerative effects. 6.2 Gene-enhanced MSCs and exosome-based therapies Another strategy to augment bone regeneration in impaired bone disorders is the use of enhanced MSCs (gene-based). Such modified cells can potentially improve resistance to ischemia and decrease the activity of progenitors in necrotic lesions by enhancing the expression of osteogenic or angiogenic factors (65). As reported by Yang et al., initial results show better bone formation and vascularization with the help of the improved cells compared to the unmodified ones, which provides a reason to develop the cells further (66). Exosome-based therapies offer a cell-free alternative with enhanced paracrine signaling, eliminating cell survival and engraftment issues associated with cell-based therapies. Exosomes are also associated with molecules that regulate osteogenesis, angiogenesis, and inflammation, and their stability can contribute to the storage and delivery of these molecules (67). Exosomes can serve as a standardized and easily accessible regenerative solution; however, further studies are needed. 6.3 Advanced scaffolds and 3D engineered constructs Sankaranarayanan et al. reported that SCT can enhance the biological and mechanical impact of SCT to the maximum when the scaffolds are in a 3D format to support the necrotic area (68).

    Stem cell therapies for biological repair in osteonecrosis: advances, challenges, and clinical insights · 2026 · DOI

  • The present review supports the central conclusion that the role of MSCs in cancer is determined primarily by context rather than by fixed intrinsic properties. Within tumors, MSCs are not uniformly tumor-promoting or tumor-suppressive but are highly plastic stromal components whose behavior is continuously shaped by inflammatory mediators, hypoxia-driven chemokine gradients, programs, and cell–matrix interactions in the TME.

    Rearming mesenchymal stem cells with engineering strategies to combat cancer · 2026 · DOI

  • First, our study provides a preliminary observation of how ACLF patient serum affects the core biological functions of MSCs; how- ever, the precise molecular signalling pathways down- stream of AOPP-induced oxidative stress remain to be fully elucidated.

    Altered Properties of Bone Marrow-Derived Mesenchymal Stem Cells Exposed to Serum from Patients with Acute-On-Chronic Liver Failure · 2026 · DOI

  • Future studies should focus on elucidating cell-microenvironment interaction-driven mechanisms that constrain ADMSC function, systematically assessing the safety and therapeutic efficacy of ADMSCs and their derivatives, and developing optimization strategies to enhance resistance to pathological stress, such as CRISPR-based genetic modification, exogenous preconditioning, and engineered MSC platforms.

    Adipose-derived mesenchymal stromal cell-microenvironment interaction network in metabolic syndrome: ADMSC injury response, adaptive regulation, and regenerative potential · 2026 · DOI

  • This study has several limitations that should be acknowl- edged. First, the number of samples included was relatively low, which may affect the statistical power and generaliz- ability of the findings. Additionally, the study design was observational, limiting the ability to establish causal rela- tionships. Future studies with larger cohorts and experimen- tal approaches are warranted to validate and expand upon these results.

    Molecular and Cellular Analysis of Lipogems-Processed Lipoaspirates for Evaluating the Efficacy of Treatments in Regenerative Medicine · 2026 · DOI

  • There is an absence of a universally accepted dose metric for EV therapeutics—whether based on particle number, protein content, or functional bioactivity.

    Mesenchymal stromal cells in Rheumathology: Recent findings · 2026 · DOI

  • The intrinsic heterogeneity of EV populations (e.g., exosomes versus microvesicles and mixed particle fractions) must be addressed in EV-based therapeutics.

    Mesenchymal stromal cells in Rheumathology: Recent findings · 2026 · DOI

  • Particle counts alone are insufficient to characterize EV products, and comprehensive analytical frameworks are required to ensure reproducibility and comparability between studies.

    Mesenchymal stromal cells in Rheumathology: Recent findings · 2026 · DOI

  • For a considerable time, MSCs have been deemed therapeutic as standalone tools to treat various conditions. The current state of the knowledge on MSC biology suggests that they do not act alone to a promote microenvironment of instigates M2 macrophages that carry on the regenerative process. PSGs that appear to be overlooked as MSC-secreted molecules instead, help the establish development repair but, tissue that Frontiers in Cell and Developmental Biology 04 frontiersin.org da Silva Meirelles 10.3389/fcell.2026.1798621 FIGURE 2 Evidence framework for a proposed mechanism of M2 macrophage polarization induced by pregnancy-specific glycoproteins produced by mesenchymal stromal cells (MSCs). Experimental findings one and six have been demonstrated in vitro and in vivo. Experimental findings two to five have been observed in vitro. integrate this complex system. Further research on PSGs could not only advance the understanding of the events involved in wound healing, but also provide opportunities the development of novel approaches to treat a wide range of diseases, including cancer.

    Pregnancy-specific glycoproteins as molecular links between mesenchymal stromal cells and M2 macrophages in tissue repair: implications for cancer progression · 2026 · DOI

  • Future directions include multicenter trials with sufficient power, uniformity of stem cell products (particularly MSCs), and synchronous endpoints [28]. Assessment of potency-based dosing (linking in vitro quantitative functional assays of live tissue to in vivo response) should be associated with treatment arm performance metrics in the phase 2 study [18]. Use of multiple biomarkers to determine the mechanism of action (immunomodulation vs. neurotrophic support vs. EVs) should also be explored [28]. MSC-exosome or MSC-based therapies, as possible safer and more controllable “cell-free” biopharmaceutical products, should be investigated through extensive clinical evaluation [28]. Combined approaches (i.e., MSCs/exosomes + rehabilitation; combined MSCs/exosomes + neuromodulation therapy; combined MSCs/exosomes + targeted anti-inflammatory therapy) should also be evaluated using factorial designs [28].

    Mesenchymal Stem Cell Therapy in Parkinson’s Disease: A Comprehensive Review · 2026 · DOI

  • Even though OC-MSCs have revealed more significant potential than other MSCs, more comprehensive, target-oriented interinstitutional prospective studies are warranted to determine whether oral cavity–derived stem cells are the most excellent sources of significant angiogenic potential.

    Angiogenic Potential of Various Oral Cavity–Derived Mesenchymal Stem Cells and Cell-Derived Secretome: A Systematic Review and Meta-Analysis · 2023 · DOI

  • 1851623 a foundation for further investigation into the potential applications of USCs in regenerative medicine.

    Effects of hypoxia on the biological characteristics of urine-derived stem cells · 2026 · DOI

  • Despite this growing characteristics of USCs under hypoxic conditions—an essential aspect of injured tissue microenvironments—remain inadequately understood.

    Effects of hypoxia on the biological characteristics of urine-derived stem cells · 2026 · DOI

  • Umbilical cord-derived mesenchymal stem cells (UC-MSCs) show therapeutic potential, but their mechanism of action is remains incompletely understood.

    Human Umbilical Cord Mesenchymal Stem Cells in Metabolic Dysfunction-associated Fatty Liver Disease (MAFLD) Therapy: Mechanisms, Clinical Efficacy, and Future Perspectives · 2026 · DOI

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60 open questions have been extracted from the limitations and future-work passages of 406 Mesenchymal stem cell research papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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