A humanized engineered heart tissue platform for cardiotoxicity assessment

Stem Cell Reports · 2026-03-19

Cardiovascular diseases (CVDs), many of which are influenced by exposure to environmental xenobiotics, lack physiologically relevant in vitro models for cardiotoxicity assessment. Although some pollutants have established associations with CVD, the effects of a wide range of potential toxicants remains unknown. Here, we developed a three-dimensional recellularized humanized engineered heart tissue (rHHT) platform by integrating decellularized human left ventricular extracellular matrix with human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), yielding spontaneously contracting tissues that recapitulate key features of native ventricular myocardium. We also generated a hiPSC line stably expressing the calcium indicator GCaMP6f, enabling real-time and longitudinal monitoring of calcium transients. Using ethanol and rotenone as examples, we demonstrate that the rHHT platform provides a sensitive system for evaluating cardiotoxicity and is more stringent than conventional monolayer approaches. This study presents a scalable platform for xenobiotic cardiotoxicity assessment, with potential applicability to high-throughput screening, mechanistic studies, and future personalized medicine applications.

Feasibility and safety of cellular therapy for in-utero repair of myelomeningocele (CuRe Trial): a first-in-human, phase 1, single-arm study

The Lancet · 2026-02-01 · 2 citations

BACKGROUND: The Management of Myelomeningocele Study (MOMS) trial established the benefit of in-utero repair of myelomeningocele, with a decreased need for ventriculoperitoneal shunt placement. However, although there was some improvement of motor function, over half of the patients were unable to ambulate independently. Live placenta-derived mesenchymal stem cells (PMSCs) seeded on an extracellular matrix have shown promise in rescuing neurological function in the fetal ovine model of myelomeningocele. We aimed to evaluate the safety of this novel, living, stem cell product to augment the prenatal repair of myelomeningocele. METHODS: In this phase 1, first-in-human, single-dose, single-arm study, pregnant women who had fetuses diagnosed with myelomeningocele were enrolled in a staggered manner at University of California, Davis (UC Davis) School of Medicine, in Sacramento (CA, USA). Eligibility criteria were gestational age from 19 weeks to 26 weeks, upper boundary of the myelomeningocele defect between T1 and S1, hindbrain herniation shown by MRI, and normal karyotype. In-utero repair of the myelomeningocele was conducted with a single dose of topically applied allogeneic human PMSCs seeded on an extracellular matrix (Cook Biodesign Dural Graft [Cook Biotech; West Lafayette, IN, USA]). The PMSCs were generated from donated placentas collected from consented patients at the UC Davis Medical Center, and the cells were tested for identity, sterility, and viability 72 h before surgery. Primary safety endpoints included evaluation of the myelomeningocele repair site for healing, cerebrospinal fluid leak, infection, and unexpected abnormal growth or tumour formation. This study is registered with ClinicalTrials.gov (NCT04652908). FINDINGS: weeks) by caesarean delivery. At birth, all infants had an intact repair site with no evidence of cerebrospinal fluid leak, infection, or abnormal tissue growth. After treatment, MRIs showed reversal of hindbrain herniation and no evidence of tumour formation. No cell-mediated adverse events occurred. INTERPRETATION: This first-in-human treatment consisting of allogeneic, live stem cells showed no cell-related adverse effects. The therapy was assessed as sufficiently safe to proceed with non-staggered enrolment of 35 patients in a phase 1/2a trial. FUNDING: California Institute for Regenerative Medicine and Shriners Children's.

A Phase I Study of CD19 CAR T-Cells with Escalating Doses of Lymphodepletion with or without Rituximab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Transplantation and Cellular Therapy · 2025-02-01

Randomized Study of Intravitreal Autologous CD34+ Stem Cells in Central Retinal Vein Occlusion (Treatment of Retinal vein occlusion Using STem cells [TRUST] Report 1): Safety and Feasibility

Ophthalmology Science · 2025-08-05

Purpose: To assess the safety and feasibility of intravitreal injection of autologous CD34+ bone marrow stem cells (BMSCs) in eyes with vision loss from central retinal vein occlusion (CRVO). Design: Phase I/II single-center, prospective, randomized, sham-controlled, double-masked study. Participants: Participants with CRVO of 6 to 42 months duration, best-corrected visual acuity (VA) of 20/40 to 20/400, and no concurrent retinopathy or optic neuropathy contributing to vision loss in the study eye. The exclusion criteria include any concurrent systemic condition that would alter bone marrow components. Methods: Participants were randomized to immediate cell injection followed by sham injection at month 6 or immediate sham injection followed by cell injection at month 6. Cell injection consisted of a bone marrow aspiration and intravitreal injection of autologous CD34+ BMSCs. CD34+ BMSCs were isolated from the mononuclear cell fraction of bone marrow using Miltenyi CliniMACS system under current good manufacturing practices. Isolated cells were released for intravitreal injection if they passed the release criteria for quantity, sterility, and viability accepted by the US Food and Drug Administration. Sham injection consisted of a sham bone marrow aspiration and intravitreal injection without entering bone or eye. Eye examination, microperimetry, fundus photography, fluorescein angiography, electroretinography, OCT, and OCT angiography were performed at baseline and during study follow-up of 12 months. Main Outcome Measures: Adverse events (AEs) associated with study treatment, number of CD34+ BMSCs injected intravitreally. Results: Sixteen participants (16 eyes) were randomized to 1 of 2 study groups. All received intravitreal injection of autologous CD34+ BMSCs (mean 4.3 million cells) and completed the study follow-up. Rubeosis with vitreous hemorrhage occurred in 1 study eye, <1 month after sham injection and 7 months after cell injection, attributed to normal progression of CRVO. There were no other serious ocular AEs. The most common AE related to the study cell injection was new floaters (15/16, 93%). Other ocular AEs were similarly noted after sham injection. No eye had persistent VA loss of ≥15 letters after cell injection. Conclusions: Intravitreal injection of autologous CD34+ BMSCs appears well-tolerated and feasible in eyes with vision loss from CRVO. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Investigational New Drug-enabling studies to use genetically modified mesenchymal stromal cells in patients with critical limb ischemia

Stem Cells Translational Medicine · 2025-02-01 · 4 citations

Mesenchymal stromal cells (MSCs) have been tested in multiple clinical trials to treat peripheral artery disease, especially the more severe form called critical limb ischemia. However, MSCs have often not met the expected efficacy endpoints. We developed a more potent therapeutic by genetically modifying MSCs to overexpress Vascular Endothelial Growth Factor (VEGF-A165). Here, we report preclinical studies submitted to the Food and Drug Administration (FDA) as part of our Investigational New Drug submission package. In vitro studies included the characterization of cell banks, transcriptome and secretome analysis, and in vitro potency assays. In vivo studies using immune-deficient NSG mice include dose-finding efficacy studies using a Matrigel plug model, cell retention studies, measurements of circulating VEGF, and toxicology studies to rule out severe adverse events. Our results suggest both the safety and efficacy of MSC/VEGF and support a first-in-human clinical trial to test this new combined cell/gene therapy.

Fibroblast Growth Factor Bioactivity Measurements Using Live-Cell Biosensor Imaging

GEN Biotechnology · 2025-04-01

Growth factor proteins are essential reagents for cell culture and tissue engineering but require quality control for bioactivity. Currently, growth factor bioactivity measurements made by immunoblot or ELISA are limited in evaluating the kinetics and heterogeneity of cellular responses, and there is a need for convenient methods with higher temporal and spatial resolution. In this study, we evaluate the advantages of using genetically encoded biosensors to quantify growth factor bioactivity in living cells. Using fibroblasts expressing a FRET-based biosensor of ERK activity, we compare methods for quantifying the cellular response across several doses and sources of recombinant basic fibroblast growth factor (bFGF). In contrast to immunological methods, the biosensor-based approach provides single-cell ERK activity kinetics and robust dose-response curves with minimal experimental processing. We additionally demonstrate that this method can assess bFGF activity in induced pluripotent stem cells and resolve spatial activity patterns. We conclude that biosensors represent a rapid, high-quality bioactivity assay extendable to other growth factors and signaling pathways.

ISCT MSC committee statement on the US FDA approval of allogenic bone-marrow mesenchymal stromal cells

Cytotherapy · 2025-01-18 · 39 citations

Long-Term Engraftment of Cryopreserved Human Neurons for In Vivo Disease Modeling in Neurodegenerative Disease

Biology · 2025-02-19 · 2 citations

The transplantation of human neurons into the central nervous system (CNS) offers transformative opportunities for modeling neurodegenerative diseases in vivo. This study evaluated the survival, integration, and functional properties of cryopreserved forebrain GABAergic neurons (iGABAs) derived from human induced pluripotent stem cells (iPSCs) across three species used in translational research. iGABAs were stereotactically injected into the striatum of Sprague-Dawley rats, immunodeficient RNU rats, R6/2 Huntington's disease (HD) mice, wild-type controls, and Cynomolgus monkeys. Post-transplantation, long-term assessments revealed robust neuronal survival, extensive neurite outgrowth, and integration with host CNS environments. In immunodeficient rats, iGABAs innervated the neuraxis, extending from the prefrontal cortex to the midbrain, while maintaining mature neuronal phenotypes without uncontrolled proliferation. Similarly, grafts in nonhuman primates showed localized survival and stable phenotype at one month. In the neurodegenerative milieu of HD mice, iGABAs survived up to six months, projecting into the host striatum and white matter, with evidence of mutant huntingtin aggregates localized within the graft, indicating pathological protein transfer. These findings underscore the utility of cryopreserved iGABAs as a reproducible, scalable model for disease-specific CNS investigations and mechanistic studies of proteinopathic propagation. This work establishes a critical platform for studying neurodegenerative diseases and developing therapeutic interventions.

Durable HTT silencing using non-evolved dCas9 epigenome editors in patient-derived cells

Molecular Therapy — Nucleic Acids · 2025-05-14 · 1 citations

was achieved in patient-derived neuronal stem cells, showing the efficacy of this system in a disease-relevant cell type. This approach represents a novel therapeutic pathway for the treatment of HD.

Fate and function of exogenously administered mesenchymal stromal cells: current insights and future directions

Cytotherapy · 2025-11-20