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Human umbilical cord blood (CB) and umbilical cord tissue (UC) are attractive sources of somatic stem cells for gene and cell therapies. CB and UC can be obtained noninvasively from donors. CB, a known source of hematopoietic stem cells for transplantation, has attracted attention as a new source of immune cells, including universal chimeric antigen receptor-T cell therapy (CAR-T) and, more recently, universal CAR-natural killer cells. UC-derived mesenchymal stromal cells (UC-MSCs) have a higher proliferation potency than those derived from adult tissues and can be used anon-HLA restrictively. UC-MSCs meet the MSC criteria outlined by the International Society of Gene and Cellular Therapy. UC-MSCs are negative for HLA-DR, CD80, and CD86 and have an immunosuppressive ability that mitigates the proliferation of activated lymphocytes through secreting indoleamine 2,3-dioxygenase 1 and prostaglandin E2, and the expression of PD-L2 and PD-L1. We established the off-the-shelf cord blood/cord bank IMSUT CORD to support novel cell therapy modalities, including the CB-derived immune cells, MSCs, MSCs-derived extracellular vesicles, biological carriers loaded with chemotherapy drugs, prodrug, oncolytic viruses, nanoparticles, human artificial chromosome, combinational products with a scaffold, bio3D printing, and so on.Human umbilical cord blood (CB) and umbilical cord tissue (UC) are attractive sources of somatic stem cells for gene and cell therapies. CB and UC can be obtained noninvasively from donors. CB, a known source of hematopoietic stem cells for transplantation, has attracted attention as a new source of immune cells, including universal chimeric antigen receptor-T cell therapy (CAR-T) and, more recently, universal CAR-natural killer cells. UC-derived mesenchymal stromal cells (UC-MSCs) have a higher proliferation potency than those derived from adult tissues and can be used anon-HLA restrictively. UC-MSCs meet the MSC criteria outlined by the International Society of Gene and Cellular Therapy. UC-MSCs are negative for HLA-DR, CD80, and CD86 and have an immunosuppressive ability that mitigates the proliferation of activated lymphocytes through secreting indoleamine 2,3-dioxygenase 1 and prostaglandin E2, and the expression of PD-L2 and PD-L1. We established the off-the-shelf cord blood/cord bank IMSUT CORD to support novel cell therapy modalities, including the CB-derived immune cells, MSCs, MSCs-derived extracellular vesicles, biological carriers loaded with chemotherapy drugs, prodrug, oncolytic viruses, nanoparticles, human artificial chromosome, combinational products with a scaffold, bio3D printing, and so on.

Peripheral nerve injuries involving nerve defects remain challenging to treat. Although autologous nerve grafting is considered the gold standard, it has notable limitations, including donor site morbidity. To address this, we developed a scaffold-free Bio 3D conduit composed of human umbilical cord–derived mesenchymal stromal cells (UC-MSCs) using bioprinting technology. In this study, we evaluated its efficacy and safety in a canine ulnar nerve defect model. At 10 weeks postoperatively, the Bio 3D group showed better motor and sensory recovery compared with the allograft group, as demonstrated by the pinprick test, electrophysiological studies, and hypothenar muscle wet weight (0.978 ± 0.100 vs. 0.637 ± 0.151, n = 3). Morphometric analysis revealed greater axonal regeneration, including larger myelinated axon diameters (4.27 ± 0.342 µm vs. 3.69 ± 0.161 µm, n = 3) and thicker myelin sheaths (0.621 ± 0.088 µm vs. 0.497 ± 0.021 µm, n = 3). Immunostaining showed that the number of transplanted UC-MSCs diminished over time, likely after exerting their therapeutic effects. No adverse events, systemic abnormalities, or distant human cell migration was observed. These findings suggest that UC-MSC–derived Bio 3D conduits are a promising alternative for peripheral nerve regeneration, especially for patients wishing to avoid donor nerve harvesting.

This study investigated the safety, efficacy, and immunological influence of allogeneic umbilical cord-derived mesenchymal stromal cells (IMSUT-CORD) processed in serum-free medium and cryoprotectant, for treating steroid-resistant acute graft-versus-host disease (aGVHD). In a phase I dose-escalation trial, IMSUT-CORD were infused intravenously twice weekly over two cycles with up to two additional cycles. Four patients received a dose of 1 × 106 cells/kg, while three received 2 × 106/kg. Of 76 total adverse events, fourteen associated or possibly associated adverse events included 2 cases of a hot flash, headache, and peripheral neuropathy, 1 each of upper abdominal pain, hypoxia, increased γ-GTP, somnolence, peripheral vascular pain at the injection site, thrombocytopenia, hypertension, and decreased fibrinogen. At 16 weeks after the initial IMSUT-CORD infusion, three patients showed complete response (CR), two partial response (PR), one mixed response, and one no response. The overall response rate was 71.4%, and the continuous CR/PR rate was 100% for over 28 days after CR/PR. NK cell count significantly increased and correlated with treatment response, whereas IL-12, IL-17, and IL-33 levels decreased, but did not correlate with treatment response. CCL2 and CCL11 levels increased during IMSUT-CORD therapy. IMSUT-CORD are usable in patients with steroid-resistant aGVHD (UMIN000032819: https://www.umin.ac.jp/ctr).

Human umbilical cord–derived mesenchymal stromal cells (UC-MSCs), which can be prepared in advance and are presumed to be advantageous for nerve regeneration, have potential as a cell source for Bio 3D conduits. The purpose of this study was to evaluate the nerve regeneration ability of Bio 3D conduits made from UC-MSCs using a rat sciatic nerve defect model. Methods: A Bio 3D conduit was fabricated using a Bio 3D printer by placing UC-MSC spheroids into thin needles according to predesigned 3D data. The conduit was transplanted to bridge the 5-mm gaps of Lewis rat sciatic nerve, and nerve regeneration was evaluated at 8 weeks (Bio 3D group). Transplantation of autologous nerve segments (autograft) and silicone tubes represented the positive and negative control groups, respectively. In a second experiment, immunological reactions were evaluated in Bio 3D, autograft, and allograft groups by histochemical staining of transplanted segments in Brown Norway rats. Results: The mean angle of attack value in the kinematic analysis was significantly better in the Bio 3D group (‒20.1 ± 0.5°) than in the silicone group (‒33.7 ± 1.5°) 8 weeks after surgery. The average diameters of myelinated axons were significantly larger in the Bio 3D group (3.61 ± 0.15 μm) than in the silicone group (3.07 ± 0.12 μm), and the number of myelinated axons was significantly higher in the Bio 3D group (11,201 ± 980) than in the silicone group (8117 ± 646). Histological findings (hematoxylin and eosin [HE] staining and anti-CD3 fluorescent immunostaining) showed that rejection was suppressed in the Bio 3D group compared to the allograft group. Based on macroscopic findings and histological findings (anti-human mitochondrial fluorescent immunostaining), UC-MSCs in the Bio 3D conduit disappeared gradually from week 1 to week 8. Conclusions: The Bio 3D conduit prepared from UC-MSCs was superior to the silicone tube and achieved comparable nerve regeneration to the autologous (autograft) group. Rejection was suppressed in the Bio 3D group compared to the allograft group. Although this study used a xenograft model, we speculate that rejection was low due to the characteristics of UC-MSCs. UC-MSCs are a useful cell source for Bio 3D conduits.

To assess safety in vaccine development, stricter grading scales, such as the “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” issued by the U.S. Food and Drug Administration (FDA grading scale), are required. However, concern exists that their strictness may lead to an overestimation of some adverse events (AEs). We analyzed the details of AEs in a phase I clinical trial of a preventive vaccine for infectious diseases. In this trial, we observed the high occurrence of Grade 1 or greater AEs in hemoglobin changes from baseline value, and hypernatremia, and hypokalemia by FDA grading scale. The range considered as non-AE according to the FDA grading scale shifted or became narrower when compared to reference intervals, especially for a Japanese cohort. For sodium grading, the criterion for hypernatremia was around 2 to mEq/L lower than the upper limit of most standards in several countries. Also, the criterion for hypokalemia was around 0.2 mEq/L higher than the lower limit of most standards. Regarding a decrease in hemoglobin from baseline, the criterion of “any decrease” used for a Grade 1 AE was too strict and we suggest this be omitted. Upper and lower limits of AE criteria for sodium and potassium should be equal to, or 10–20% above, the reference interval consistent with other toxicities determined by laboratory tests. Consideration should be given to the issues surrounding the criteria that determine AEs before conducting clinical trials.

Introduction: Mesenchymal stromal cells (MSCs) are activated upon inflammation and/or tissue damage and migrate to suppress inflammation and repair tissues. Migration is the first important step for MSCs to become functional; however, the migration potency of umbilical cord-derived MSCs (UC-MSCs) remains poorly understood. Thus, we aimed to assess the migration potency of UC-MSCs in comparison with those of bone marrow-derived MSCs (BM-MSCs) and adipose tissue-derived MSCs (AD-MSCs) and investigate the influence of chemotactic factors on the migration of these cells. Methods: We compared the migration potencies of UC-, BM-, and AD-MSCs toward allogeneic stimulated mononuclear cells (MNCs) in mixed lymphocyte reaction (MLR). The number of MSCs in the upper chamber that migrated toward the MLR in the lower chamber was counted using transwell migration assay. Results and discussion: UC-MSCs showed significantly faster and higher proliferation potencies and higher migration potency toward unstimulated MNCs and MLR than BM- and AD-MSCs, although the migration potencies of the three types of MSCs were comparable when cultured in the presence of fetal bovine serum. The amounts of CCL2, CCL7, and CXCL2 in the supernatants were significantly higher in UC-MSCs co-cultured with MLR than in MLR alone and in BM- and AD-MSCs co-cultured with MLR, although they did not induce the autologous migration of UC-MSCs. The amount of CCL8 was higher in BM- and AD-MSCs than in UC-MSCs, and the amount of IP-10 was higher in AD-MSCs co-cultured with MLR than in UC- and BM-MSCs. The migration of UC-MSCs toward the MLR was partially attenuated by platelet-derived growth factor, insulin-like growth factor 1, and matrix metalloproteinase inhibitors in a dose-dependent manner. Conclusion: UC-MSCs showed faster proliferation and higher migration potency toward activated or non-activated lymphocytes than BM- and AD-MSCs. The functional chemotactic factors may vary among MSCs derived from different tissue sources, although the roles of specific chemokines in the different sources of MSCs remain to be resolved.

The development of stem cell therapies is evolving rapidly in parallel with advances in stem cell biology. However, many important issues remain to be addressed, ranging from the detailed molecular dissection of the therapeutic capabilities of stem cells in situ, through to the selection of both patients and sources of cells for clinical trials. Particularly pertinent to patient selection is the importance of enrolling sufficient numbers of patients in clinical trials, especially for comparative studies. Unfortunately, conducting comparative studies is often complicated by limitations on cell processing or the relative rarity of target diseases, so it is difficult to enroll sufficient numbers of patients with diverse backgrounds. Indeed, the number of patients enrolled in comparative stem cell studies is generally small, and few randomized trials have been conducted. In Japan, a new regulatory framework involving conditional and time-limited approval of regenerative products and mandatory post-marketing surveillance after early approval may help resolve the problem, because the enrollment qualification data for many patients will be collected. The translation of stem cell therapies to the clinic is still in its infancy, and stringent efforts to identify and establish suitable patient and control cohorts from diverse genetic, ethnic, and demographic backgrounds remain a high priority for the optimization of clinical trial design.

ObjectiveTo investigate under what circumstances inappropriate use of ‘multivariate analysis’ is likely to occur and to identify the population that needs more support with medical statistics.Study design and settingsThe frequency of inappropriate regression model construction in multivariate analysis and related factors were investigated in observational medical research publications.ResultsThe inappropriate algorithm of using only variables that were significant in univariate analysis was estimated to occur at 6.4% (95% CI 4.8% to 8.5%). This was observed in 1.1% of the publications with a medical statistics expert (hereinafter ‘expert’) as the first author, 3.5% if an expert was included as coauthor and in 12.2% if experts were not involved. In the publications where the number of cases was 50 or less and the study did not include experts, inappropriate algorithm usage was observed with a high proportion of 20.2%. The OR of the involvement of experts for this outcome was 0.28 (95% CI 0.15 to 0.53). A further, nation-level, analysis showed that the involvement of experts and the implementation of unfavourable multivariate analysis are associated at the nation-level analysis (R=−0.652).ConclusionBased on the results of this study, the benefit of participation of medical statistics experts is obvious. Experts should be involved for proper confounding adjustment and interpretation of statistical models.

Cancer metastasis is intricately orchestrated by both cancer and normal cells, such as endothelial cells and macrophages. Monocytes/macrophages, which are often co-opted by cancer cells and promote tumor malignancy, acquire more than half of their energy from glycolysis even during normoxic conditions. This glycolytic activity is maintained during normoxia by the functions of hypoxia inducible factor 1 (HIF-1) and its activator APBA3. The mechanism by which APBA3 inhibition partially suppresses macrophage function and affects cancer metastasis is of interest in view of avoidance of the adverse effects of complete suppression of macrophage function during therapy. Here, we report that APBA3-deficientmice show reduced metastasis,with no apparent effect on primary tumor growth. APBA3 deficiency in inflammatory monocytes, which strongly express the chemokine receptor CCR2 and are recruited toward chemokine CCL2 from metastatic sites, hampers glycolysis-dependent chemotaxis of cells toward metastatic sites and inhibits VEGFA expression, similar to the effects observed with HIF-1 deficiency. Host APBA3 induces VEGFA-mediated E-selectin expression in the endothelial cells of target organs, thereby promoting extravasation of cancer cells and micrometastasis formation. Administration of E-selectin–neutralizing antibody also abolished host APBA3-mediated metastatic formation. Thus, targeting APBA3 is useful for controlling metastatic niche formation by inflammatory monocytes.

We retrospectively compared transplant outcomes for related bone marrow transplantation (rBMT), related peripheral blood stem cell transplantation (rPBSCT), unrelated bone marrow transplantation (uBMT), and unrelated cord blood transplantation (CBT) in 1,062 patients with chronic myeloid leukemia (CML) aged 20 years or over between January 1, 2000 and December 31, 2009 in Japan. The disease status was as follows: chronic phase 1 (CP1, n  = 531), CP 2 or later including accelerated phase (CP2-AP, n  = 342) and blastic crisis (BC, n  = 189). Graft sources (GS) were rBMT ( n  = 205), uBMT ( n  = 507), rPBSCT ( n  = 226) or CBT ( n  = 124). In multivariate analysis in CP1, lower overall survival (OS) (relative risk [RR]: 6.01, 95 % confidence interval [CI]: 1.20–29.97, P  = 0.029) and leukemia-free survival (LFS) (RR: 4.26, 95 % CI: 1.24–14.62, P  = 0.021) were observed in uBMT compared with those in rBMT. For patients in the advanced phase of CML beyond CP1, GS had no significant impact on OS or LFS. Our results support the use of rBMT for adults with CML in CP1, but in contrast to previous reports, the superiority of rPBSCT in advanced stage of CML was not confirmed in our cohorts.