Small‐sized mesenchymal stem cells with high glutathione dynamics show improved therapeutic potency in graft‐versus‐host disease

Chai

Clinical & Translational Med

et al. 2021

Background The heterogeneity of mesenchymal stem cells (MSCs) is poorly understood, thus limiting clinical application and basic research reproducibility. Advanced single‐cell RNA sequencing (scRNA‐seq) is a robust tool used to analyse for dissecting cellular heterogeneity. However, the comprehensive single‐cell atlas for human MSCs has not been achieved. Methods This study used massive parallel multiplexing scRNA‐seq to construct an atlas of > 130 000 single‐MSC transcriptomes across multiple tissues and donors to assess their heterogeneity. The most widely clinically utilised tissue resources for MSCs were collected, including normal bone marrow ( n = 3), adipose ( n = 3), umbilical cord ( n = 2), and dermis ( n = 3). Results Seven tissue‐specific and five conserved MSC subpopulations with distinct gene‐expression signatures were identified from multiple tissue origins based on the high‐quality data, which has not been achieved previously. This study showed that extracellular matrix (ECM) highly contributes to MSC heterogeneity. Notably, tissue‐specific MSC subpopulations were substantially heterogeneous on ECM‐associated immune regulation, antigen processing/presentation, and senescence, thus promoting inter‐donor and intra‐tissue heterogeneity. The variable dynamics of ECM‐associated genes had discrete trajectory patterns across multiple tissues. Additionally, the conserved and tissue‐specific transcriptomic‐regulons and protein‐protein interactions were identified, potentially representing common or tissue‐specific MSC functional roles. Furthermore, the umbilical‐cord‐specific subpopulation possessed advantages in immunosuppressive properties. Conclusion In summary, this work provides timely and great insights into MSC heterogeneity at multiple levels. This MSC atlas taxonomy also provides a comprehensive understanding of cellular heterogeneity, thus revealing the potential improvements in MSC‐based therapeutic efficacy.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Single‐cell transcriptome atlas of human mesenchymal stem cells exploring cellular heterogeneity

Chai

Clinical & Translational Med

et al. 2021

“…pDONR223_ID2_WT_V5 for the human ID2 ORF was a gift from Jesse Boehm, Matthew Meyerson & David Root (Addgene plasmid # 82960) 15 . Lentivirus was produced using a four-plasmid transfection system (Invitrogen) and concentrated using an Lenti-X Concentrator Kit (Clontech, Mountain View, CA, USA) as previously described 16 – 18 . Gene expression and functional assays were performed 4 days after lentiviral infection.…”

Section: Methodsmentioning

confidence: 99%

The CDK1/TFCP2L1/ID2 cascade offers a novel combination therapy strategy in a preclinical model of bladder cancer

et al. 2022

Self Cite

Aberrant activation of embryogenesis-related molecular programs in urothelial bladder cancer (BC) is associated with stemness features related to oncogenic dedifferentiation and tumor metastasis. Recently, we reported that overexpression of transcription factor CP2-like protein-1 (TFCP2L1) and its phosphorylation at Thr177 by cyclin-dependent kinase-1 (CDK1) play key roles in regulating bladder carcinogenesis. However, the clinical relevance and therapeutic potential of this novel CDK1-TFCP2L1 molecular network remain elusive. Here, we demonstrated that inhibitor of DNA binding-2 (ID2) functions as a crucial mediator by acting as a direct repressive target of TFCP2L1 to modulate the stemness features and survival of BC cells. Low ID2 and high CDK1 expression were significantly associated with unfavorable clinical characteristics. TFCP2L1 downregulated ID2 by directly binding to its promoter region. Consistent with these findings, ectopic expression of ID2 or treatment with apigenin, a chemical activator of ID2, triggered apoptosis and impaired the proliferation, suppressed the stemness features, and reduced the invasive capacity of BC cells. Combination treatment with the specific CDK1 inhibitor RO-3306 and apigenin significantly suppressed tumor growth in an orthotopic BC xenograft animal model. This study demonstrates the biological role and clinical utility of ID2 as a direct target of the CDK1-TFCP2L1 pathway for modulating the stemness features of BC cells.

Stem Cells Translational Medicine

“… 9 , 29 Using autologous MSCs might be safer than using allogenic MSCs, but the challenges of hampered engraftment and survival of transplanted cells remain. Large-scale production of MSCs derived from adult tissues has limits in maintaining primitive function and proliferative capacities, 11 , 12 especially if the cells are obtained from tissues of an aged donor. Moreover, MSCs that undergo higher passage numbers are more likely to provoke an innate immune attack upon transplantation.…”

Section: Discussionmentioning

confidence: 99%

Safety of Human Embryonic Stem Cell-derived Mesenchymal Stem Cells for Treating Interstitial Cystitis: A Phase I Study

Shin

Ryu

et al. 2022

There are still no definite treatment modalities for interstitial cystitis (IC). Meanwhile, stem cell therapy is rising as potential alternative for various chronic diseases. This study aimed to investigate the safety of the clinical-grade mesenchymal stem cells (MSCs) derived from human embryonic stem cells (hESCs), code name MR-MC-01 (SNU42-MMSCs), in IC patients. Three female IC patients with (1) symptom duration >6 months, (2) visual pain analog scale (VAS) ≥4, and (3) one or two Hunner lesions <2 cm in-office cystoscopy within 1 month were included. Under general anesthesia, participants received cystoscopic submucosal injection of SNU42-MMSCs (2.0 × 107/5 mL) at the center or margin of Hunner lesions and other parts of the bladder wall except trigone with each injection volume of 1 mL. Follow-up was 1, 3, 6, 9, and 12 months postoperatively. Patients underwent scheduled follow-ups, and symptoms were evaluated with validated questionnaires at each visit. No SNU42-MMSCs-related adverse events including immune reaction and abnormalities on laboratory tests and image examinations were reported up to 12-month follow-up. VAS pain was temporarily improved in all subjects. No de novo Hunner lesions were observed and one lesion of the first subject was not identifiable on 12-month cystoscopy. This study reports the first clinical application of transurethral hESC-derived MSC injection in three patients with IC. hESC-based therapeutics was safe and proved to have potential therapeutic efficacy in IC patients. Stem cell therapy could be a potential therapeutic option for treating IC.