CytotherapyPub Date : 2025-03-20DOI: 10.1016/j.jcyt.2025.03.003
Fei Yang, Xi Jia, Ying Liu, Shenghao Hua, Weixi Li, Xuejun Shao, Qi Wang
{"title":"CCRL2 deficiency and dyslipidemia: implications for thrombocytopenia post allo-HSCT.","authors":"Fei Yang, Xi Jia, Ying Liu, Shenghao Hua, Weixi Li, Xuejun Shao, Qi Wang","doi":"10.1016/j.jcyt.2025.03.003","DOIUrl":"https://doi.org/10.1016/j.jcyt.2025.03.003","url":null,"abstract":"<p><strong>Background: </strong>Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been the most effective treatment for refractory hematologic diseases. Thrombocytopenia (TP) and dyslipidemia are common complications that affect the prognosis of patients after allo-HSCT. The chemokine (c-c motif) receptor-like 2 (CCRL2) has various roles in immune and inflammatory responses, while its function in thrombopoiesis after allo-HSCT has not been reported. Therefore, this study investigated the role of CCRL2 in thrombopoiesis under conditions of dyslipidemia.</p><p><strong>Methods: </strong>Differentially expressed genes in bone marrow-derived nucleated cells were analysed using next-generation RNA sequencing. Enzyme-linked immunosorbent assay (ELISA) was used to detect the concentrations of thrombopoietin (TPO) or chemerin. CCRL2 and ApoE double knockout (CCRL2<sup>-/-</sup>ApoE<sup>-/-</sup>) mice were generated by crossing CCRL2<sup>-/-</sup> mice with ApoE<sup>-/-</sup> mice. Inflammatory cytokines, megakaryocyte (MK) polyploidization, and reactive oxygen species (ROS) levels were assessed by flow cytometry. Giemsa staining of human bone marrow smears and hematoxylin and eosin (H&E) staining of paraffin-embedded murine bone marrow slices were performed to identify MK morphology. Immunoblotting was employed to analyze autophagic protein levels by detecting LC3.</p><p><strong>Results: </strong>CCRL2 was significantly downregulated in platelets and MKs of TP children with impaired megakaryopoiesis, severe dyslipidemia, and strong cytokine storms. Platelet counts and high-ploidy MKs in CCRL2<sup>-/-</sup>ApoE<sup>-/-</sup> mice were significantly reduced compared to CCRL2<sup>+/+</sup>ApoE<sup>-/-</sup> and CCRL2<sup>+/+</sup>ApoE<sup>+/+</sup> mice, accompanied by decreased ROS levels and increased autophagic protein expression.</p><p><strong>Conclusion: </strong>Our results demonstrated that both CCRL2 and lipid homeostasis are closely related to thrombopoiesis, and may provide potential targets for the prevention of TP after allo-HSCT.</p>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"CD34-selected stem cell boost was an effective treatment for refractory poor hematopoietic reconstitution after haploidentical hematopoietic stem cell transplantation.","authors":"Yun He, Rui Ma, Yuanyuan Zhang, Huan Chen, Yao Chen, Yuhong Chen, Tingting Han, Wei Han, Fengrong Wang, Haixia Fu, Chenhua Yan, Meng Lv, Xiaodong Mo, Yifei Cheng, Yu Wang, Lanping Xu, Xiaohui Zhang, Xiaojun Huang, Yuqian Sun","doi":"10.1016/j.jcyt.2025.03.004","DOIUrl":"https://doi.org/10.1016/j.jcyt.2025.03.004","url":null,"abstract":"<p><strong>Background: </strong>Poor hematopoietic reconstitution (PHR), especially poor graft function (PGF) and prolonged isolated thrombocytopenia (PT), is a life-threatening complication after allo- hematopoietic stem cell transplantation (HSCT). Currently, almost no studies have analyzed CD34+-selected stem cells \"boost\" (SCB) after haplo-HSCT. Hence, in this study, we focused specifically on refractory PHR after haplo-HSCT.</p><p><strong>Objective: </strong>To retrospectively evaluate the safety and efficacy of donor- CD34+ SCB for the treatment of refractory PHR after haplo-HSCT.</p><p><strong>Study design: </strong>Twenty-seven patients with refractory PHR who received a donor-CD34+ selected SCB at Peking University People's Hospital were retrospectively analyzed. The patients' hematopoietic response, incidence of graft-versus-host disease, and survival after CD34+ cell boost were evaluated.</p><p><strong>Results: </strong>Among the 27 patients with refractory PHR who received a CD34+ SCB, five patients (18.5%) were diagnosed with primary PGF, 17 patients (63%) were diagnosed with secondary PGF, and five patients (18.5%) were diagnosed with PT. The median time to PHR diagnosis was 63 days (range: 42-330 days), and the median time to the donor CD34+ boost was 456 days (range: 58-853 days). The median number of infused CD34+ cells was 2.589 × 10<sup>6</sup>/kg (range: 0.738-16.8 × 10<sup>6</sup>/kg). Among the 27 patients, 15 achieved hematologic response (55.56%). Among the responders, the median time of absolute neutrophil count (ANC) response was 15 days (range: 10-158 days), and the median time of erythroid reconstitution was 18 days (range: 7-158 days). The platelet reconstitution time was 22 days (range: 7-171 days). Patients with acute infection during CD34+ SCB were noted to have a worse hematologic response (1/15 vs. 5/12, P = 0.03). The mortality rate significantly differed between patients who achieved complete hematologic response and those who did not (100% vs. 33.3%, respectively; P < 00.001). Infections were the leading cause of death (n = 5/8, 62.5%).</p><p><strong>Conclusion: </strong>CD34+-selected SCB is a potentially effective treatment for refractory PHR after haploidentical HSCT.</p>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Center effect on outcomes of second allogeneic hematopoietic stem cell transplantation for B-cell acute lymphoblastic leukemia: a nationwide retrospective study.","authors":"Shuhei Kurosawa, Takahiro Fukuda, Tatsuo Ichinohe, Yoshiko Hashii, Junya Kanda, Hideki Goto, Koji Kato, Fumihiko Ishimaru, Makoto Yoshimitsu, Moeko Hino, Keitaro Matsuo, Yuri Ito, Atsumi Yanagisawa, Marie Ohbiki, Ken Tabuchi, Yoshiko Atsuta, Yasuyuki Arai","doi":"10.1016/j.jcyt.2025.03.002","DOIUrl":"https://doi.org/10.1016/j.jcyt.2025.03.002","url":null,"abstract":"<p><p>We evaluated the impact of center volume on outcomes in patients with B-cell acute lymphoblastic leukemia following their second allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our cohort included 299 patients with relapse and 68 patients with graft failure after their first allo-HSCT between 2003 and 2017. Patients were stratified into low- and high-volume groups based on the number of allo-HSCT performed at each center. The primary endpoint was 5-year overall survival (OS) following the second allo-HSCT. In the relapse cohort, the high-volume group demonstrated significantly better 5-year OS (21.1% vs 13.6%, P = 0.0062) and progression-free survival (16.1% vs 10.6%, P = 0.010). Multivariate analysis showed that high-volume group was a favorable factor for OS (hazard ratio [HR]: 0.72, 95% confidence interval [CI]: 0.56-0.94, P = 0.016). This survival benefit was consistent in both Philadelphia chromosome-negative (HR: 0.71, 95% CI: 0.51-0.99, P = 0.042) and positive (HR: 0.61, 95% CI: 0.39-0.95, P = 0.030) subcohorts. In the graft failure cohort, the high-volume group showed a trend toward better 5-year OS (41.6% vs 24.4%, P = 0.098) and lower 5-year nonrelapse mortality (NRM) (55.9% vs 75.6%, P = 0.067). Multivariate analysis confirmed the protective effect of the high-volume group on NRM (HR: 0.55, 95% CI: 0.30-0.99, P = 0.044). Our findings demonstrate that center volume significantly impacts outcomes after the second allo-HSCT regardless of indication, highlighting the need for inter-center collaboration and standardized management strategies for this high-risk population.</p>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CytotherapyPub Date : 2025-03-07DOI: 10.1016/j.jcyt.2025.02.009
Nicholas D Cober, Ketul R Chaudhary, Yupu Deng, Chyan-Jang Lee, Katelynn Rowe, Haya Abdelwahab, David W Courtman, Duncan J Stewart
{"title":"Single-cell microencapsulation improves lung retention of endothelial colony-forming cells after intravascular delivery and unmasks therapeutic benefit in severe pulmonary arterial hypertension.","authors":"Nicholas D Cober, Ketul R Chaudhary, Yupu Deng, Chyan-Jang Lee, Katelynn Rowe, Haya Abdelwahab, David W Courtman, Duncan J Stewart","doi":"10.1016/j.jcyt.2025.02.009","DOIUrl":"https://doi.org/10.1016/j.jcyt.2025.02.009","url":null,"abstract":"<p><p>Pulmonary arterial hypertension (PAH) is triggered by pulmonary vascular endothelial cell apoptosis and microvascular loss. Therefore, therapies that can regenerate lost vasculature may offer therapeutic benefit. Endothelial colony-forming cells (ECFCs) can directly repair damaged blood vessels and may have therapeutic potential for the treatment of PAH. However, poor retention of ECFCs in the lungs following intravenous delivery greatly limits their therapeutic application. Therefore, we studied whether cellular microencapsulation could enhance retention in the lung after systemic delivery and improve therapeutic efficacy of ECFCs in a rat monocrotaline (MCT) PAH model. ECFCs were encapsulated by vortex emulsion using various concentrations of agarose, and initial cell viability was assessed. Encapsulated and free ECFCs were transduced with luciferase and administered to Sprague-Dawley rats 3 days after injection of MCT. In vivo ECFC persistence and bio-distribution was assessed by bioluminescence imaging (BLI). At the end of the study, right ventricular systolic pressure (RVSP) and right ventricular hypertrophy were assessed for therapeutic efficacy. Microgel encapsulation using 3.5% agarose improved cell survival and supported cell migration from capsules. At 15 minutes after delivery, BLI radiance was similar for free and microencapsulated ECFCs. However, only encapsulated cells could be detected by BLI at 4 and 24 hours. Transplantation of microencapsulated ECFCs led to significant improvement in RVSP 3 weeks after delivery compared with nonencapsulated ECFCs. Together, microencapsulation increased retention of ECFCs within the lungs. Furthermore, even a modest increase in ECFC persistence over 24 hours can provide an important therapeutic benefit in the rat MCT model of PAH.</p>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Regulatory advancements in Japan's conditional and time-limited approval scheme for regenerative medical products: the first guidance on the approval scheme and the second review for full approval of the first conditional and time-limited approved cellular product, HeartSheet.","authors":"Shinichi Noda, Yoko Kobayashi, Narumi Okura, Kayo Shinohara, Junichi Asano, Jun Matsumoto","doi":"10.1016/j.jcyt.2025.02.010","DOIUrl":"https://doi.org/10.1016/j.jcyt.2025.02.010","url":null,"abstract":"<p><p>In Japan, the Act on Securing Quality, Efficacy, and Safety of Products including Pharmaceuticals and Medical Devices (PMD Act) provides the option for an expedited approval scheme, conditional and time limited, for regenerative medical products only. In March 2024, the Guidance for Conditional and Time-Limited Approval for Regenerative Medical Products and the Development of Subsequent Efficacy Evaluation Plan was established by the Ministry of Health, Labor and Welfare (MHLW). This document is the first guidance on the approval scheme, providing information such as specific examples of the scope of this scheme as well as an indication of what should be considered in the post-marketing approval condition assessment. HeartSheet-a human (autologous) skeletal myoblast-derived cell sheet-was the first product approved through the conditional and time-limited approval scheme. After the second review by the Pharmaceuticals and Medical Devices Agency (PMDA) based on post-marketing data, the MHLW decided in July 2024 that the product had not demonstrated efficacy and that full approval was not appropriate. This is the first time that post-marketing data have been considered for the full approval of a conditional and time-limited approval product. This decision demonstrates that the conditional and time-limited approval scheme is strictly enforced. This article describes key points of the guidance on the conditional and time-limited approval scheme and the PMDA's full approval review experience with HeartSheet. These regulatory actions will further deepen the understanding of the conditional and time-limited approval scheme, especially among developers, and promote more appropriate use of the scheme.</p>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Effects of a PDGF-stem cell-hydrogel compound on skin wound healing in mice.","authors":"Jiaqi Lin, Ziwei Lin, Anqi Huang, Xinyi Wu, Wei Yan, Daojun Liu, Chiju Wei, Wencan Xu","doi":"10.1016/j.jcyt.2025.01.001","DOIUrl":"https://doi.org/10.1016/j.jcyt.2025.01.001","url":null,"abstract":"<p><strong>Background aims: </strong>The treatment of chronic refractory skin wounds still remains a serious clinical challenge. Stem cells and hydrogels are widely used in healing of skin wound of various types due to their superior bioactivities and biocompatibility. This study aimed to demonstrate the wound healing effect of a hydrogel compound loaded with enucleated stem cells expressing the platelet-derived growth factor (PDGF).</p><p><strong>Methods: </strong>An injectable hydrogel was formulated using 22% poloxamer 407, 1% poloxamer 188, and 1% hyaluronic acid. A PDGF-B transgenic cell line of mouse bone marrow mesenchymal stem cells (BMSCs) was generated by lentiviral infection. Cells were enucleated and embedded in hydrogel. The healing effects of the compound was tested in a full-thickness skin wound model of Balb/c mice. The wound models were randomly divided into four groups: the control group applied with PBS buffer; the hydrogel group with hydrogel only; the BMSC group with hydrogel mixed with normal BMSCs; and the BMSC-PDGF group with hydrogel mixed with enucleated BMSCs expressing PDGF.</p><p><strong>Results: </strong>Overexpression of PDGF-B in transgenic cell line of BMSCs was verified by RT-PCR, immunofluorescence staining and western blot. When enucleated, the viability measured by Calcein-AM staining reduced to 54.29% at 48 h. Conditioned medium was collected with or without hydrogel layered over cells. PDGF concentration measured by ELISA reached 14.66 ng/μL and 257.89 ng/μL respectively after 48-h cultivation, suggesting a possible slow releasing effect in the presence of hydrogel. When applied to the skin wound, the healing rates of the BMSC-PDGF group was significantly higher than that of the control group on day 3. BMSC-PDGF group had significantly more neovascularization and cutaneous appendages from day 7. The proliferation of collagen fibers in BMSC-PDGF group was significantly higher than the control group on day 3 and day 7. Finally, BMSC-PDGF group had significantly lower amount of the inflammatory factors TNF-α, IL-1β, IL-6, MMP-3 and MMP-9 than that of the control group on day 7.</p><p><strong>Conclusions: </strong>PDGF-stem cell-hydrogel compound significantly improved wound healing and reduced wound inflammatory factor expression in Balb/c mice. This biomaterial-based approach provides a new powerful reference for the treatment of chronically wounded skin.</p>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CytotherapyPub Date : 2025-02-24DOI: 10.1016/j.jcyt.2025.02.007
Mieszko Lachota, Radosław Zagożdżon
{"title":"Synthetic receptor-based cell therapies for autoimmune diseases: an update.","authors":"Mieszko Lachota, Radosław Zagożdżon","doi":"10.1016/j.jcyt.2025.02.007","DOIUrl":"https://doi.org/10.1016/j.jcyt.2025.02.007","url":null,"abstract":"<p><p>Increasing frequency of autoimmune diseases is one of the major problems in modern societies. Despite the introduction of new therapeutic agents for autoimmunity over the past several decades, more progress is needed. Synthetic receptor-based cell therapies are being adopted as an option for treating autoimmune diseases from the field of oncology. Currently evaluated strategies can be summarized into two approaches. The first one is the elimination of autoreactive cells by targeting them, for example, with CAR-T or CAAR-T cells. The second is based on rebalancing the proinflammatory milieu with engineered immunosuppressive cells, for example, CAR-Treg. Both approaches can be supplemented with the use of synthetic systems such as Split-CAR, SynNotch, MESA, GEMS, and SNIPR, or prospective off-the-shelf approaches, for example, in situ use of the in vitro transcribed mRNA, ultimately allowing for enhanced efficacy and safety. The primary goal of our review is to provide some perspective on both strategies in basic, translational, and clinical studies with all their advantages and disadvantages to allow for informed future design of adoptive cell therapies for autoimmune diseases.</p>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"HGF-DPSCs ameliorate asthma by regulating CCR1<sup>+</sup> Th2 cells responses in mice pulmonary mucosa.","authors":"Geng Lin, Mengyu Tao, Heqiang Sun, Xinli Deng, Letong Zhang, Guixiang Sun, Yong Zhou, Guogang Xu","doi":"10.1016/j.jcyt.2025.02.005","DOIUrl":"10.1016/j.jcyt.2025.02.005","url":null,"abstract":"<p><p>Asthma, a prevalent allergic disease affecting approximately 300 million individuals globally, remains a significant public health challenge. Mesenchymal stromal cells (MSCs) and hepatocyte growth factor (HGF), both recognized for their immunomodulatory properties, hold therapeutic potential for asthma. However, their precise mechanisms remain underexplored. The current study aimed to engineer human HGF overexpressing human dental pulp stromal cells (HGF-DPSCs) and evaluate their efficacy in asthma management while elucidating underlying mechanisms. The results showed that the constructed HGF-DPSCs overexpressed HGF both in vitro and in vivo. Also, compared with DPSCs, they demonstrated a more pronounced distribution within lung tissue. In house dust mite (HDM)-induced asthma, HGF-DPSCs showed a more significant inhibitory effect on airway hyperresponsiveness (AHR), inflammatory infiltration, and CD4<sup>+</sup> T-cell recruitment compared with DPSCs. Immunofluorescence analysis revealed a spatial overlap between HGF-DPSCs and pulmonary epithelial cells. Protein array analysis identified the chemokine Ckβ8-1 as a pivotal factor in the interaction between HGF-DPSCs and bronchial epithelial Beas-2B cells. Subsequent mechanistic investigations demonstrated that administration of HGF-DPSCs markedly reduced both the expression of Ckβ8-1 protein and the proportion of CD4<sup>+</sup>CCR1<sup>+</sup> T lymphocytes in the lungs of asthmatic mice. Furthermore, transwell migration assays incorporating a CKβ8-1 antagonist revealed a significant inhibition of CD4<sup>+</sup> T-cell migration. Flow cytometry analysis indicated that CD4<sup>+</sup>CCR1<sup>+</sup> T cells from the lungs of asthmatic mice exhibit a pronounced Th2 phenotype, characterized by high expression levels of IL-4, IL-5, and IL-13 cytokines. In conclusion, HGF-DPSCs ameliorate HDM-induced asthma by suppressing CCR1<sup>+</sup> Th2 cell responses via modulation of the Ckβ8-1/CCR1 axis, highlighting their potential as a novel therapeutic strategy.</p>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}