Article of the Year 2020
Paracrine Mechanisms of Mesenchymal Stromal Cells in AngiogenesisRead the full article
Stem Cells International publishes papers in all areas of stem cell biology and applications. The journal publishes basic, translational, and clinical research, including animal models and clinical trials.
Chief Editor Professor Li has a background in cardiac stem cell transplantation, using young stem cells to promote tissue repair following injury to rejuvenate the aged individual, and the development of biomaterials that can easily integrate into damaged heart tissue.
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METTL3-Mediated m6A RNA Modification Regulates Corneal Injury Repair
Limbal stem cells are essential for continuous corneal regeneration and injury repair. METTL3-catalyzed N6-methyladenosine (m6A) mRNA modifications are involved in many biological processes and play a specific role in stem cell regeneration, while the role of m6A modifications in corneal injury repair remains unknown. In this study, we generated a limbal stem cell-specific METTL3 knockout mouse model and studied the role of m6A in repairing corneal injury caused by alkali burn. The results showed that METTL3 knockout in the limbal stem cells promotes the in vivo cell proliferation and migration, leading to the fast repair of corneal injury. In addition, m6A modification profiling identified stem cell regulatory factors AHNAK and DDIT4 as m6A targets. Our study reveals the essential functions of m6A RNA modification in regulating injury repair and provides novel insights for clinical therapy of corneal diseases.
SOX12 Promotes Stem Cell-Like Phenotypes and Osteosarcoma Tumor Growth by Upregulating JAGGED1
SOX12 plays a role in promoting the growth of some tumors; however, its role in osteosarcoma remains unclear. From gene expression omnibus (GEO) and tumor alterations relevant for genomics-driven therapy (TARGET) databases, Kaplan–Meier analyses were conducted to establish relationships between SOX12 expression and osteosarcoma survival and recurrence in osteosarcoma patients. We also performed in vitro and in vivo assays to determine SOX12 function in osteosarcoma etiology. SOX12 expression was increased in osteosarcoma; high SOX12 expression levels were related to a poor prognosis and a high disease recurrence in patients. Moreover, SOX12 expression in osteosarcoma cell lines was increased, similar to osteosarcoma cancer stem cells. We also observed that SOX12 knockdown inhibited the spheroidization and expression of stemness markers in osteosarcoma cells and tumor formation in nude mice. In addition, SOX12 knockdown inhibited JAGGED1 and HES1 expression. Similarly, JAGGED1 knockdown also inhibited the formation of osteosarcoma cancer stem cells into pellets and reduced the expression of stemness markers and tumor formation capabilities in nude mice. Finally, during SOX12 knockdown, JAGGED1 overexpression rescued osteosarcoma cells from spheroidizing. SOX12 promotes stem cell-like phenotypes and osteosarcoma tumor growth by upregulating JAGGED1.
miR-20a Overexpression in Adipose-Derived Mesenchymal Stem Cells Promotes Therapeutic Efficacy in Murine Lupus Nephritis by Regulating Autophagy
Objective. Lupus nephritis is the most common and severe complication of systemic lupus erythematosus. The aim of our study was to investigate the efficacy of miR-20a overexpressing adipose-derived stem cell (ADSC) transplantation in murine lupus nephritis (LN) and explore potential molecular mechanisms. Methods. Mouse ADSCs were transfected with a miR-20a lentiviral vector to obtain miR-20a overexpression ADSCs (miR-20a-ADSCs). We first observed the influence of miR-20a on ADSC viability and apoptosis in vitro. B6.MRL/lpr mice were administered ADSC/miR-20a-ADSC intravenously every week from age 30 to 33 weeks, and the lupus and normal control groups received PBS on the same schedule. Results. miR-20a expression increased in miR-20a-ADSC-derived exosomes, and miR-20a overexpression promoted ADSC proliferation and inhibited apoptosis. Compared with ADSCs, miR-20a-ADSC treatment significantly improved serologic and histologic abnormalities, as evidenced by reduced serum creatinine, anti-dsDNA antibody, 24 h urine protein levels, nephritis scores, and C3/IgG deposits. Furthermore, miR-20a-ADSC treatment resulted in downregulated Akt, mTOR, and p62 expression and upregulated miR-20a, Beclin 1, and LC3 II/I expression compared with ADSC treatment. After treatment with miR-20a-ADSC, a significant increase in the number of autophagosomes within podocytes was observed, along with upregulated expression of podocin and nephrin, compared with the ADSC group. Conclusions. miR-20a-ADSC transplantation prevents the development of lupus nephritis and significantly ameliorates already-established disease, and its mechanism is related to autophagy by targeting the miR-20a-regulated mTOR pathway.
Human Umbilical Mesenchymal Stromal Cells Mixed with Hyaluronan Transplantation Decreased Cartilage Destruction in a Rabbit Osteoarthritis Model
Osteoarthritis (OA), the most common type of arthritis, causes pain in joints and disability. Due to the absence of ideal effective medication, stem cell transplantation emerges as a new hope for OA therapy. This study is aimed at evaluating the capability of human umbilical cord mesenchymal stromal cells (HUCMSCs) mixed with hyaluronan (HA) to treat osteoarthritis in a rabbit model. Differentiation capability of HUCMSCs, magnetic resonance image examination, and immunohistochemistry of the cartilage after transplantation of HUCMSCs mixed with HA in a rabbit OA model were explored. HUCMSCs exhibited typical mesenchymal stromal cell (MSC) characteristics, including spindle-shaped morphology, surface marker expressions (positive for human leukocyte antigen- (HLA-) ABC, CD44, CD73, CD90, and CD105; negative for HLA-DR, CD34, and CD45), and trilineage differentiation (chondrogenesis, adipogenesis, and osteogenesis). The gene expression of SOX9, type II collagen, and aggrecan in the HUCMSC-derived chondrocytes mixed with HA was increased after in vitro chondrogenesis compared with HUCMSCs. A gross and histological significant improvement in hyaline cartilage destruction after HUCMSCs mixed with HA was noted in the animal model compared to the OA knees. The International Cartilage Repair Society histological score and Safranin O staining were significantly higher for the treated knees than the control knees (). Moreover, the expression of MMP13 was significantly decreased in the treated knees than in the OA knees. In conclusion, HUCMSCs mixed with HA in vitro and in vivo might attenuate the cartilage destruction in osteoarthritis. Our study provided evidence for future clinical trials.
Characteristics of Mesenchymal Stem Cells Are Independent of Bone Marrow Storage Temperatures
Mesenchymal stem cells play an important role in regenerative medicine due to their capability of self-renewal and multipotent differentiation. For research or clinical application, bone marrow aspirates are harvested during elective surgeries to isolate MSCs. If an immediate purification of the MSCs is not possible, the bone marrow must be stored. Therefore, the aim of this study was to investigate possible differences of stem cell characteristics regarding the self-renewal capability, the adipogenic, chondrogenic, and osteogenic differentiation, and the expression of surface antigens after different storage conditions of the bone marrow aspirates. Three groups were analysed: the first group was purified immediately after harvesting, the other two groups were processed after they were stored 18 to 24 hours at 22°C (room temperature) or at 4°C. Comparisons between the groups were performed using the Kruskal-Wallis test for nonparametric data. The final results showed no significant difference between the different storage conditions. Therefore, storage of bone marrow aspirates for 18 to 24 hours at room temperature or 4°C is possible without loss of stem cell characteristics.
Retinal Lineage Therapeutic Specific Effect of Human Orbital and Abdominal Adipose-Derived Mesenchymal Stem Cells
Retinal degenerative diseases are one of the main causes of complete blindness in aged population. In this study, we compared the therapeutic potential for retinal degeneration of human mesenchymal stem cells derived from abdominal subcutaneous fat (ABASCs) or from orbital fat (OASCs) due to their accessibility and mutual embryonic origin with retinal tissue, respectively. OASCs were found to protect RPE cells from cell death and were demonstrated to increase early RPE precursor markers, while ABASCs showed a raise in retinal precursor marker expression. Subretinal transplantation of OASCs in a mouse model of retinal degeneration led to restoration of the RPE layer while transplantation of ABASCs resulted in a significant restoration of the photoreceptor layer. Taken together, we demonstrated a lineage-specific therapeutic effect for either OASCs or ABASCs in retinal regeneration.