Cell Technology (China)

Cerebral palsy (CP), the most prevalent pediatric motor disorder with significant cognitive comorbidity (> 50%), lacks therapies addressing both impairments in moderate-to-severe cases. This study demonstrates that human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) exert profound therapeutic effects in a rat model of moderate-to-severe CP established via bilateral carotid artery occlusion with hypoxia. Intravenously administered hUCMSC-Exos displayed sustained brain retention and significantly restored motor coordination and cognitive function. The recovery was primarily mediated through enhanced remyelination driven by promoted oligodendrocyte maturation and differentiation (elevated oligodendrocyte lineage transcription factor 2 and myelin basic protein). Concurrently, the treatment attenuated key pathological processes involving sustained neuroinflammatory responses (reduced ionized calcium-binding adapter molecule 1, tumor necrosis factor-α, and interleukin-6) while elevating brain-derived neurotrophic factor. Our findings establish hUCMSC-Exos as a promising dual-modality therapy for moderate-to-severe CP, mechanistically linked to robust remyelination and coordinated modulation of core disease mechanisms.

ABSTRACT Aims Among individuals with type 2 diabetes mellitus (T2DM), the prevalence of metabolic dysfunction‐associated steatotic liver disease (MASLD) is disproportionately high, contributing to increased vulnerability toward cirrhosis and, ultimately, primary liver cancer. Early identification of hepatic fibrosis in such patients is therefore of paramount importance. We aimed to explore clinical determinants of fibrosis in patients with T2DM and MASLD and examine chitinase‐3‐like protein 1 (CHI3L1) as a potential indicator of fibrotic progression. Methods This retrospective study included patients with T2DM who initially visited Tianjin Third Central Hospital (January 2023–August 2024). Liver fibrosis was assessed both across the entire T2DM cohort and among those with coexisting MASLD, based on liver stiffness measurement (LSM) and noninvasive indicators, such as aspartate aminotransferase‐to‐platelet ratio index (APRI), fibrosis‐4 (FIB‐4) index, and CHI3L1. An LSM threshold of 8 kPa was used to identify significant liver fibrosis (SLF). Associations between LSM, CHI3L1, and other indicators were examined by correlation analysis. Risk factors of liver fibrosis were determined by logistic regression analyses, and the discriminative ability of CHI3L1 was evaluated using receiver operating characteristic curve analysis. Results The cohort comprised 236 patients with T2DM, including 176 with concomitant MASLD (74.6%) and 89 with SLF (37.7%). In the T2DM–MASLD group, 74 (42.0%) patients had SLF, with significantly elevated weight, body mass index (BMI), thyroid‐stimulating hormone (TSH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma‐glutamyl transferase (GGT), lactate dehydrogenase (LDH), total bilirubin (TBIL), direct bilirubin (DBIL), FIB‐4, CHI3L1, APRI, LSM, and controlled attenuation parameter (CAP), and reduced systolic blood pressure (SBP), platelet count (PLT), low‐density lipoprotein cholesterol (LDL‐C), and platelet‐to‐white blood cell ratio (PWR), compared with their fibrosis‐free counterparts (all p < 0.05). A significant positive correlation was observed between CHI3L1 expression and LSM ( r = 0.48, p < 0.001). Multivariate analysis identified CHI3L1 (odds ratio [OR] = 1.84, 95% confidence interval [CI]: 1.209–2.809, p = 0.004), APRI (OR = 2.71, 95% CI: 1.629–4.529, p < 0.001), and CAP (OR = 2.63, 95% CI: 1.612–4.317, p < 0.001) as independent determinants of fibrosis risk. The predictive capacity of CHI3L1 showed an area under the curve (AUC) of 0.717 (95% CI: 0.638–0.796, p < 0.05), corresponding to a cutoff value of 96.6 ng/mL. Conclusion A substantial share of patients with T2DM were diagnosed with MASLD, while some had SLF. Patients with fibrosis had higher BMI, CHI3L1, AST, LDH, TSH, APRI, LSM, and CAP levels than those without. Notably, serum CHI3L1 correlated significantly with fibrosis and may function as a biomarker for disease progression.

Despite intriguing roles for the Succinate receptor (Sucnr1) in inflammation, few studies have explored its role in hematopoiesis. Here, we show that low SUCNR1 represents a marker for reduced overall and progression-free survival in acute myeloid leukemia (AML) patients. Succinic acid, which displays Sucnr1-dependent and independent effects, promotes disease in mouse models of pre-leukemic myelopoiesis, AML and AML xenografts, expressing low SUCNR1. In vivo global or hematopoietic deletion of Sucnr1 induces expansion of hematopoietic stem and progenitor cells (HSPC) and hematopoiesis, whilst Sucnr1-tomato+ HSPC display restricted engraftment potential. Mechanistically, activation of Sucnr1 counterbalances the stimulatory effect of intracellular succinate in HSPC and preserves HSPC transcriptional programs via control of S100a8/S100a9. Blocking S100a9 with tasquinimod rescues the defects of Sucnr1 knock-out mice, and combined with a potent Sucnr1 agonist shows therapeutic value in AML mice. In AML xenografts, single-cell RNA-sequencing reanalyses confirm SUCNR1 as a therapeutic vulnerability in patients. Together, Sucnr1 signaling restricts hematopoiesis at least partially through HSPC and via control of S100a8/S100a9. Its dysregulation emerges as contributor to malignancy that opens therapeutic avenues for AML patients.

NPM1-mutated acute myeloid leukemia (AML) is a distinct entity with specific biological and clinicopathological features. Prognosis varies depending on the associated mutations and clinical characteristics. This study evaluated the prognostic factors of NPM1-mutated AML in patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We enrolled 139 patients with NPM1-mutated AML who underwent allo-HSCT. The median age at allo-HSCT was 47 years with a median follow-up of 1,134 days. The 3-year cumulative incidence of relapse (CIR), leukemia-free survival (LFS), and overall survival (OS) rates were 15.1%, 78.4%, and 78.0%, respectively. FLT3-ITD mutations showed higher CIR (22.6% vs 5.3%, P = 0.006), lower LFS (70.9% vs 88.1%, P = 0.019), and reduced OS (70.8% vs 87.5%, P = 0.036). FLT3-ITD and DTA mutations indicated adverse prognosis, while IDH1/2 mutations showed improved outcomes. Matched sibling donor (MSD) allo-HSCT patients had higher CIR and lower LFS and OS than unrelated donor (URD) or haploidentical-related donor (HRD) recipients. Pre-HSCT MRD status affected the outcomes, with MRD+ and nCR patients showing worse outcomes. Multivariable analysis identified FLT3-ITD, MSD, and pre-MRD status as significant predictors. In conclusion, FLT3-ITD and DTA mutations are associated with an adverse prognosis, whereas HRD or URD transplants may offer better outcomes than MSD allo-HSCT.

Rationale: Phospholipase A2 receptor (PLA2R) is the predominant autoantigen in primary membranous nephropathy (PMN), accounting for approximately 70% of clinical cases. However, the mechanisms by which PLA2R initiates and sustains autoimmunity in PMN remain unclear. PLA2R belongs to the mannose receptor (MR) family, members of which have been shown to undergo endocytosis and lysosomal degradation for MHCII-mediated antigen presentation. This study investigates whether antibody binding promotes PLA2R internalization and lysosomal processing to enhance MHCII-mediated antigen presentation and CD4⁺ T cell activation, thereby contributing to the perpetuation of autoimmunity in PMN. Methods: Multiple PLA2R-overexpressing cell lines were generated by lentiviral-mediated overexpression of PLA2R. Imaging and western blot were employed to assess the effects of anti-PLA2R antibodies, derived from PMN patients or produced in-house, on PLA2R internalization and degradation. To define the specific endocytic pathway involved, we used pharmacological inhibitors of endocytosis as well as PLA2R constructs lacking the endocytic domain. Finally, T cell activation was evaluated using OT-II CD4⁺ T cells co-cultured with PLA2R-ovalbumin (OVA)-expressing mouse dendritic cells treated with anti-PLA2R antibodies. Results: Binding of anti-PLA2R antibodies triggers clathrin-mediated endocytosis and lysosomal trafficking of PLA2R. Antibody-induced PLA2R degradation was effectively prevented by specific endocytosis inhibitors or by deletion of the PLA2R endocytic domain. Furthermore, PLA2R-OVA-expressing mouse dendritic cells exposed to PLA2R antibodies enhanced the activation of OVA-specific CD4⁺ T cells both in vitro and in vivo. Conclusions: This study demonstrates that anti-PLA2R antibody induces internalization and lysosomal degradation of PLA2R, a process that may enhance MHC class II-mediated antigen presentation and promote the expansion of antigen-specific CD4⁺ T cells. This mechanism could establish a self-reinforcing feedback loop that perpetuates autoimmune responses in PMN.

Abstract C 42 H 32 F 2 Fe 2 O 4 P 2 Te 2 , monoclinic, P 2 1 (no. 4), a = 10.8243(9) Å, b = 16.7702(15) Å, c = 12.1105(12) Å, β = 114.079(5) ° , ^{\circ} , V = 2007.1(3) Å 3 , Z = 2, R gt (F) = 0.0472, wR ref (F 2 ) = 0.1188, T = 293(2) K.

Mesenchymal stem cells (MSCs) are widely used in regenerative medicine, including the treatment of pulmonary fibrosis. However, implanted MSCs disappear within days, constraining therapeutic efficacy, which is largely attributed to nutrient deprivation. In this study, we established glycogen metabolism engineering strategies in mammalian cells. By expressing a functionally optimized glycogen synthase (GYSmut), MSCs could accumulate large amounts of glycogen rapidly as a reserve substance. Glycogen engineering significantly improved the survival of MSCs during starvation both in vitro and in vivo, enhancing cell viability post-implantation and their therapeutic efficacy in pulmonary fibrosis. Glycogen-engineered MSCs may serve as chassis cells for further applications. Our research highlights the importance of glucose metabolism regulation in cell-based therapy and demonstrates the great potential for the metabolic engineering of MSCs and other therapeutic cells.