Recent scientific research reveals that wrapping aged adipose-derived mesenchymal stem cells (AD-MSCs) in a "coat" from young cells—the extracellular matrix (ECM)—can significantly reverse their senescence, restoring youthful vitality.
However, a thought-provoking contradiction emerges: These stem cells, once capable of evading immune clearance and acting as "repair messengers" in the body, unexpectedly activate immune T cells after rejuvenation [1].
This creates a dramatic twist: Stem cells tasked with tissue regeneration now face the risk of being eliminated by the immune system just as they regain vitality. What is the underlying mechanism of this delicate battle for cell fate? Let’s explore the core of this scientific mystery.
1. Extracellular Matrix (ECM): The "Coat" of Cells
In the microscopic world of our bodies, the age of the ECM reflects the survival status of cells.
Aged ECM: A "Chaotic Battlefield"
The aged ECM resembles a chaotic battlefield. Senescent cells continuously release signaling molecules like pro-inflammatory factors and matrix metalloproteinases (MMPs)—components of the senescence-associated secretory phenotype (SASP). These molecules act like out-of-control demolition teams: They not only induce senescence in surrounding healthy cells but also over-degrade the local environment, eventually forming a chronic inflammatory microenvironment that hinders regeneration and repair [2].
Figure Note: Senescent cells may promote tissue and organ dysfunction through SASP (Key effects: Stem/progenitor cell depletion, systemic/tissue inflammation, senescent cell buildup, and disease-specific SASP events).
Young ECM: A Precise Regenerative Scaffold
In contrast, the young ECM is an elaborate regenerative scaffold. It is constructed from structural proteins into an ordered, moderately rigid 3D network that provides physical support and growth guidance for cells. More importantly, this scaffold embeds various growth factors and cytokines, promoting stable and orderly cell function and growth [3].
Figure Note: A. Components of the extracellular matrix (e.g., collagens, nidogen, perlecan, hyaluronic acid, glycosaminoglycans); B. How collagens, proteoglycans, laminin, and fibronectin connect within the ECM.
2. Aged AD-MSCs Rejuvenate With a "Young Coat"
In a recent study, researchers divided AD-MSCs (derived from adults over 65 years old) into two groups:
- TCP Group: Cultured in ordinary plastic dishes (tissue culture plastic).
- ECM Group: Cultured on ECM beds made primarily from the ECM of human amniotic fluid-derived pluripotent stem cells.
After five generations of expansion:
- Telomeres in the ECM group were longer than those in the TCP group.
- Levels of reactive oxygen species (ROS) and the senescence marker β-galactosidase (β-gal) were significantly reduced.
By the 7th generation, the number of cells in the ECM group was approximately 1×10⁶ times (1 million-fold) higher than that in the TCP group [1].
Figure Note: A. Cell expansion fold; B. Cell growth status after expansion; C. Telomere length of the two groups; D. ROS and β-gal levels (apoptotic cells are fluorescent green, with fewer apoptotic cells in the ECM group); E. β-gal-positive cell percentage (lower in the ECM group at all passages).
Additionally, after ECM culture, the differentiation capacity of AD-MSCs significantly improved:
- More adipocytes and osteoblasts were generated.
- By day 21 of culture, the ECM group produced larger cartilage with over 3-fold higher collagen production—like building a stronger cartilage scaffold.
- After over 10 days of culture with specific inducers, the ECM group showed increased expression of the neural marker MAP2 and developed Nissl bodies (a hallmark of neurons).
This differentiation potential—enabling aged AD-MSCs to differentiate into osteoblasts and even neurons—opens broad prospects for tissue engineering and disease treatment.
Figure Note: E. Larger cartilage in the ECM group (blue-stained area = cartilage); F. Collagen content (COL2A1 expression); G. Nissl bodies (purple spots); H. Neural marker (MSI-1) levels; I. Neural marker (MAP2) levels.
3. Feasibility of Autologous Transplantation of "Rejuvenated" Aged AD-MSCs
The study used autologous aged stem cells cultured on ECM, bringing hope for autologous transplantation in elderly patients.
AD-MSCs are a type of mesenchymal stem cell (MSC), which is regarded as a "universal repair tool" for its regenerative abilities. Autologous stem cells from elderly patients have severe defects; the traditional solution is to use allogeneic (donor-derived) MSCs. However, studies have shown that allogeneic MSCs may be cleared by the immune system and carry the risk of pathogen transmission.
As expected, subsequent tests revealed that ECM-cultured cells lost the "immune privilege" of MSCs: Their HLA-DR expression increased (MSCs typically have immune privilege and barely express HLA-DR [4]).
When ECM-cultured cells were co-cultured with allogeneic peripheral blood mononuclear cells (PBMCs), immune rejection occurred, stimulating the proliferation of allogeneic T cells.
Figure Note: D. Increased HLA-DR expression in the ECM group (8.5% in TCP vs. 76.8% in ECM); Lower panels: T cell proliferation (higher in co-cultures with ECM cells, indicating immune activation).
T cell proliferation directly reflects immune system activation. Activated T cells are likely to recognize HLA-DR-expressing stem cells as "dangerous signals" or "abnormal cells" and eliminate them—leading to the failure of transplantation.
What about autologous transplantation? Since the transplanted stem cells are derived from the patient themselves, the immune system should recognize them as "self" and likely not initiate aggressive immune rejection. Theoretically, autologous transplantation is considered "immune-privileged."
However, the study provided no data on autologous transplantation, and clinical data in this area is currently lacking. Nevertheless, for elderly patients, the therapeutic potential and application prospects of in vitro-cultured autologous stem cell transplantation remain promising.
4. Extracellular Vesicles From Young Stem Cells May Be Superior
While the role of ECM is confirmed, many studies have turned to another key mediator of intercellular communication: extracellular vesicles (EVs). EVs encapsulate abundant bioactive substances (e.g., proteins, mRNA) and deliver them precisely to target cells.
Co-culturing aged stem cells with EVs secreted by young cells yielded effects similar to ECM culture—reversing cell senescence [5].
Figure Note: Exosomes (a type of EV) derived from human umbilical cord MSCs (UMSCs) rejuvenate aged MSCs and enhance their myocardial repair function (Key mechanism: Exosomal miR-136 targets APAF1, inhibiting caspase-9 activation and promoting MSC survival/activity).
Compared to the complex-structured ECM, EVs—with their clear composition, easy isolation, and high clinical translation potential—may be a better tool for cell rejuvenation.
5. Challenges for Clinical Application
Aged MSCs not only have impaired function but may also accumulate DNA damage and epigenetic changes [6]. In vitro rejuvenation may temporarily restore some functions, but can it completely reverse these deep-seated molecular damages? The long-term safety and efficacy of infusing these "repaired but inherently aged" cells back into the body remain uncertain.
Furthermore, both young ECM and EVs face technical challenges [7]:
- Their preparation, purification, and dosing have not yet been fully standardized, leading to significant batch-to-batch variation.
- The precise molecular mechanism networks behind their effects are not fully elucidated, making risk control more difficult.
References
[1] Gonzalez, A. O., Abdul Azees, P. A., Chen, J. P., et al. (2025). Aging Adipose-Derived Mesenchymal Stem Cells, Cultured on a Native Young Extracellular Matrix, Are Protected From Senescence and Apoptosis Along With Increased Expression of HLA-DR and CD74 Associated With PI3K Signaling. Aging Cell, e70165. https://doi.org/10.1111/acel.70165[2] Birch, J., & Gil, J. (2020). Senescence and the SASP: many therapeutic avenues. Genes & Development, 34(23-24), 1565–1576. https://doi.org/10.1101/gad.343129.120[3] Walker, C., Mojares, E., & Del Río Hernández, A. (2018). Role of Extracellular Matrix in Development and Cancer Progression. International Journal of Molecular Sciences, 19(10), 3028. https://doi.org/10.3390/ijms19103028[4] Heo, J. S., Choi, Y., Kim, H. S., & Kim, H. O. (2016). Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow, umbilical cord blood, placenta and adipose tissue. International Journal of Molecular Medicine, 37(1), 115–125. https://doi.org/10.3892/ijmm.2015.2413[5] Zhang, N., Zhu, J., Ma, Q., et al. (2020). Exosomes derived from human umbilical cord MSCs rejuvenate aged MSCs and enhance their functions for myocardial repair. Stem Cell Research & Therapy, 11(1), 273. https://doi.org/10.1186/s13287-020-01782-9[6] Massidda, M. W., Demkov, A., Sices, A., et al. (2024). Mechanical Rejuvenation of Mesenchymal Stem Cells from Aged Patients. bioRxiv, 2024.06.06.597781. https://doi.org/10.1101/2024.06.06.597781[7] Cai, W., Xiao, Y., Yan, J., et al. (2024). EMF treatment delays mesenchymal stem cells senescence during long-term in vitro expansion by modulating autophagy. Frontiers in Cell and Developmental Biology, 12, 1489774. https://doi.org/10.3389/fcell.2024.1489774