Cell Transplantation最新文献

The predictive performance of the Molecular International Prognostic Scoring System (IPSS-M) for high-risk myelodysplastic syndromes (MDS) patients undergoing transplantation remains uncertain. We retrospectively analyzed 86 MDS patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at our center from 2016 to 2023. According to IPSS-M, patients were classified as Low (n = 3), Moderate-Low (n = 9), Moderate-High (n = 15), High (n = 28), and Very-High risk (n = 31). The IPSS-M did not demonstrate good prognostic accuracy for overall survival (OS) (P = 0.227) and disease-free survival (DFS) (P = 0.095) in these 86 patients. We then divided the patients into three groups based on their IPSS-M scores: IPSS-M < 0.56 (n = 28), IPSS-M 0.56-1.75 (n = 30), and IPSS-M>1.75 (n = 28). There was a significant difference in the long-term OS (P = 0.010) and DFS among the three groups (P < 0.001). This indicates that, based on the original IPSS-M scores, we may be able to find a more precise risk stratification for high-risk MDS patients undergoing allo-HSCT. Compared with TP53 wild-type and TP53 monoallelic mutations, TP53 biallelic mutations have a significant negative impact on OS and DFS (P = 0.016, P = 0.006). It is crucial to identify TP53 allelic status at diagnosis to distinguish these patients and determine the need for early involvement in clinical trials.

Mucopolysaccharidosis type IIIC (MPS IIIC) is a severe neurodegenerative lysosomal storage disease caused by the loss-of-function of the lysosomal transmembrane protein acetyl-CoA: heparan-α-glucosamine N-acetyltransferase. MPS IIIC is characterized by the accumulation of the glycosaminoglycan (GAG) heparan sulfate. There is no treatment for this disease. We generated a new MPS IIIC mouse model and confirmed disease phenotypes such as GAG accumulation, splenomegaly, neurological defects, and presence of disease-specific non-reducing end carbohydrates. To explore a new therapeutic strategy for this condition, we transplanted wild-type (WT) hematopoietic stem and progenitor cells (HSPCs) into lethally irradiated 2-month-old Hgsnat^-/- mice and analyzed the resulting impact 6 months later. Transplanted HSPCs differentiated into macrophages in tissues and microglia-like cells in the brain. This resulted in a partial restoration of Hgsnat expression and enzymatic activity along with a significant reduction of the MPS IIIC-specific non-reducing end carbohydrate in the treated Hgsnat^-/- mice compared to untreated Hgsnat^-/- mice or Hgsnat^-/- mice transplanted with Hgsnat^-/- HPSCs. In addition, WT HSPC transplant resulted in improved neurological defects, reduction in splenomegaly, and urine retention in the Hgsnat^-/- mice. Furthermore, presence of glomerular hyaline bodies with focal fibrosis and sclerosis was observed in the kidney of the disease controls, whereas these abnormalities were improved in the Hgsnat^-/- mice treated with WT HSPCs. These data support that HSPC transplantation presents a promising therapeutic avenue for MPS IIIC and represents the first step toward the clinical translation of an HSPC-mediated therapy strategy for MPS IIIC.

Although notable progress has been made, restoring motor function from the brain to the muscles continues to be a substantial clinical challenge in motor neuron diseases/disorders such as spinal cord injury (SCI). While cell transplantation has been widely explored as a potential therapeutic method for reconstructing functional motor pathways, there remains considerable opportunity for enhancing its therapeutic effectiveness. We reviewed studies on motor pathway regeneration to identify molecular and ultrastructural cues that could enhance the efficacy of cell transplantation. While the glial scar is often cited as an intractable barrier to axon regeneration, this mainly applies to axons trying to penetrate its "core" to reach the opposite side. However, the glial scar exhibits a "duality," with an anti-regenerative core and a pro-regenerative "surface." This surface permissiveness is attributed to pro-regenerative molecules, such as laminin in the basement membrane (BM). Transplanting donor cells onto the BM, which forms plastically after injury, may significantly enhance the efficacy of cell transplantation. Specifically, forming detour pathways between transplanted cells and endogenous propriospinal neurons on the pro-regenerative BM may efficiently bypass the intractable scar core and promote motor pathway regeneration. We believe harnessing the tissue's innate repair capacity is crucial, and targeting post-injury plasticity in astrocytes and Schwann cells, especially those associated with the BM that has predominantly been overlooked in the field of SCI research, can advance motor system restoration to a new stage. A shift in cell delivery routes-from the traditional intra-parenchymal (InP) route to the transplantation of donor cells onto the pro-regenerative BM via the extra-parenchymal (ExP) route-may signify a transformative step forward in neuro-regeneration research. Practically, however, the complementary use of both InP and ExP methods may offer the most substantial benefit for restoring motor pathways. We aim for this review to deepen the understanding of cell transplantation and provide a framework for evaluating the efficacy of this therapeutic modality in comparison to others.

The optimal intensity of conditioning regimens for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients diagnosed with myelodysplastic syndromes with excess blasts (MDS-EB) remains debated. We retrospectively analyzed the clinical outcomes of 102 MDS-EB patients who received an individualized conditioning protocol based on age and comorbidity, including busulfan, fludarabine, cytarabine, and low-dose total body irradiation (TBI). All patients achieved successful engraftment, with a median time to neutrophil and platelet engraftment of 12 and 13 days, respectively. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) at 180 days was 16.9%, while moderate-to-severe chronic GVHD at 2 years occurred in 15.0% of patients. After a median follow-up of 23 months, the 2-year relapse incidence was 11.5%. The 2-year overall survival (OS), progression-free survival (PFS), and GVHD-free/relapse-free survival (GRFS) were 81.9%, 77.3%, and 66.4%, respectively. The very high-risk subgroup of the International Prognostic Scoring System for MDS (IPSS-M) exhibited significantly higher relapse rates compared with the lower-risk groups (17.8% vs 2.4%, P = 0.03). Multivariate analysis identified IPSS-M as the only independent predictor of PFS (hazard ratio (HR) = 3.30, P = 0.04), whereas transplant conditioning intensity (TCI) showed no association with survival outcomes. These findings suggest that the age- and comorbidity-adjusted conditioning regimen achieves high engraftment rates, low relapse, and favorable survival in MDS-EB patients, with disease biology (IPSS-M) outweighing conditioning intensity in prognostic relevance.

Recent regulatory approvals and maturing clinical evidence indicate that mesenchymal stromal cells (MSCs) exert therapeutic effects predominantly through paracrine and immunomodulatory mechanisms rather than lineage-driven regeneration. In line with contemporary positions from International Society for Cell & Gene Therapy and Japanese Society for Regenerative Medicine, we argue for mechanism-aligned terminology and propose framing these interventions as MSC-based immunomodulatory therapies. This terminology improves scientific clarity, aligns clinical endpoints and potency assays with the mechanism of action, facilitates coherent regulatory communication, and mitigates public misunderstanding tied to the legacy "stem cell" label.

Mesenchymal stromal cells (MSCs) have been shown to exert therapeutic effects by modulating various cell types, including vascular endothelial cells, immune cells, and resident stem cells, at sites of tissue injury. Recent studies have highlighted the importance of MSC-macrophage interactions in suppressing inflammation and promoting tissue regeneration; however, the underlying mechanisms remain poorly understood. In this study, we administered MSCs intratracheally to mice with bleomycin (BLM)-induced lung injury and investigated their effects on alveolar macrophages (AvMs), defined as CD64^High/F4/80^High/Siglecf^High/CD11b^Negative. MSC transplantation alleviated loss of AvMs observed after BLM treatment. Transcriptomic profiling of AvMs revealed increased expression of genes associated with cell survival, oxidative stress resistance, and efferocytosis. Among them, Sesn2 was notably upregulated. Ex vivo experiments using isolated AvMs demonstrated that lactate treatment upregulated both Hypoxia inducible factor 1 alpha (Hif1a) and Sestrin 2 (Sesn2), and that siRNA-mediated suppression of Hif1a attenuated the lactic acid-induced increase in Sesn2 expression. These findings provide mechanistic insight into how MSCs exert tissue-protective functions via the modulation of tissue-resident macrophages, and identify Sesn2 as a key molecule involved in this process. Our study underscores the immunomodulatory capacity of MSCs and their therapeutic relevance in lung injury.

Haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) provides cure opportunity for patients requiring prompt allogeneic HSCT but failing to identify well-matched donor, but its outcomes are potentially impaired by increased transplant-related mortality (TRM). We performed haplo-HSCT using granulocyte colony-stimulating factor (G-CSF)-primed peripheral blood stem cells (PBSCs), umbilical cord mesenchymal stem cells (UC-MSCs) and third-party unrelated umbilical cord blood (UCB) stem cells. Modified "Beijing protocol" were performed in this study. All of the patients were transplanted by Busulfan or TBI-based regimen. Anti-thymocyte globulin were used to T-cell depletion in vivo. Cyclosporine, mycophenolate mofetil, and short course methotrexate were used to prevent graft-versus-host disease (GVHD). One hundred and sixty-five patients with hematological disorders undergoing haplo-HSCT from Jan 2021 to Nov 2023 were included in this study. The median time of neutrophil engraftment were 12 days (range: 9-25 days), and the median time of platelet engraftment were 13 days (range: 6-50 days). Full haploidentical donor chimerism were obtained within 30 days. No evidence of UCB chimerism was found. Twenty-five patients developed acute GVHD. The incidence of grade II-IV and grade III-IV acute GVHD was 12.73% and 6.67%, respectively. Twenty-eight patients developed chronic GVHD, 10 were limited (6.06%) and 18 were extensive (10.91%). The TRM is total of 26 deaths (15.8%) and the cumulative incidence of relapse (CIR) is total of 17 deaths (11.8%) occurred as of the statistical period. The 2 years overall survival (OS) rate is 72.96%. The median overall survival rate was not reached. Haplo-HSCT performed by PBSCs, UC-MSCs and UCB "triple-infusion" achieved excellent outcomes, and need to explored in a larger cohort.

The recent clinical success of chemically induced pluripotent stem cell (CiPSC)-derived islet transplantation for type 1 diabetes represents a landmark achievement in regenerative medicine. This article delves into the groundbreaking work presented by Dr. Hongkui Deng and Dr. Candice S.Y. Liew at International Society for Stem Cell Research (ISSCR) 2025, focusing on their innovative chemical reprogramming technology and its clinical application. The discussion highlights the scientific rationale behind chemical reprogramming, the development of functional islets, the novel transplantation strategy, and the remarkable clinical outcomes observed in their first patient. The implications for future stem cell therapies and the challenges of scalability are also explored.

Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease characterized by altered levels of inflammatory cytokines. One of the key cytokines involved in the pathogenesis of RA is tumor necrosis factor α (TNF-α), which plays a crucial role in the differentiation of T cells and B cells and serves as a primary trigger of inflammation and joint damage in RA. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have shown potential in alleviating the symptoms of RA. Previous in vitro studies indicate that TNF-α secreted by T cells can activate NF-κB in human MSCs, thereby triggering the immunoregulatory capacity of MSCs in a manner dependent on tumor necrosis factor receptor 1 (TNFR1). Inspired by these findings, we aimed to evaluate whether TNFR1 determine the therapeutic effects of hUC-MSCs on RA. First, we investigated whether TNFR1 is necessary for hUC-MSCs to inhibit TNF-α production of PBMCs, a source of elevated TNF-α in patients. Through coculture experiment, we confirmed that this inhibition was dependent on TNFR1. Subsequently, we administered hUC-MSCs or siTNFR1-MSCs to DBA/1J male mice with collagen-induced arthritis. The results indicated that hUC-MSCs significantly alleviated the pathological features of RA and suppressed the inflammatory cytokines IFN-γ, TNF-α, and IL-6 in peripheral blood, also in a manner dependent on TNFR1 either. Given the dramatic pathologic differences between hUC-MSCs and siTNFR1-MSCs treatments, we questioned whether production of growth factors and chemokines was significantly influenced by TNFR1. Consequently, we stimulated hUC-MSCs or siTNFR1-MSCs through IFN-γ, TNF-α, and IL-6, and profiled growth factors and chemokines in serum, which revealed significant changes of hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF), as well as chemokines CXCL9, CXCL10, IL-8, and RANTES. In summary, our findings suggest that TNFR1 may determine whether hUC-MSCs will gain abilities of anti-inflammation and tissue regeneration.

The trans-vessel wall device (TW-device) is a new endovascular tool for precise and safe delivery of various payloads (cells, viral, modified RNA, chemotherapy, growth factors) in oncology and regenerative medicine. The twofold aim of this study was to assess cell engraftment and tumor growth using the TW-device for endovascular transplantation and to evaluate its ability to directly access solid tumors. We used the VX2 model in the rabbit kidney to compare percutaneously implanted fresh VX2 cells with TW-device injections of cryopreserved VX2 cells. We demonstrated the feasibility of endovascular transplantation (n = 7) of tumor cells, achieving a 57.1% engraftment rate despite cryopreservation, comparable with 70% for percutaneous delivery of fresh cells (n = 10). Re-access using the TW-device was 100% successful (n = 11) with super-selective intratumoral contrast administration without complications. In conclusion, endovascular transplantation of VX2 cells using the TW-device resulted in proliferating cell grafts in the rabbit kidney establishing functional proof that cells indeed survive handling, preparation, and device passage. We also show the TW-device is able to access solid tumor parenchyma allowing precise intraparenchymal administration.This proof-of-concept study open up possibilities for repeated direct parenchymal injections via the endovascular route in any hard to reach organ.