Center of Regenerative Medicine in Barcelona

Huntington’s disease (HD) is a fatal, inherited neurodegenerative disorder marked by the progressive and selective loss of spiny projection neurons (SPNs), resulting in a characteristic triad of motor, cognitive, and psychiatric symptoms. Despite ongoing research, no disease-modifying treatments are available, and existing therapies are limited to symptomatic relief. Stem cell-based approaches represent a promising avenue to restore striatal circuitry by replacing lost neurons and/or delivering trophic support to preserve the remaining neural tissue.In this review, we present a critical analysis of past and current clinical trials exploring cell-based therapies for HD. Early studies using human fetal tissue were hindered by sample heterogeneity and inconsistent outcomes, ultimately limiting their clinical applicability. More recent trials have shifted focus toward mesenchymal stem cells (MSCs), which are valued for their neuroprotective secretome but are not suitable for neuronal replacement. To address these limitations, human pluripotent stem cells (hPSCs) have emerged as a renewable and scalable source for the development of advanced therapy medicinal products (ATMPs). In vitro differentiation protocols mimic key developmental signaling pathways to generate striatal-like neural progenitor cells (NPCs). We review the cellular composition of these hPSC-derived ATMPs and summarize findings from preclinical transplantation studies, including data on graft survival, neuronal maturation, synaptic integration, and functional recovery. In addition, we discuss other emerging strategies such as direct neuronal reprogramming. Finally, we examine the major challenges that remain—such as ensuring graft safety, consistency, and regulatory compliance—and highlight the importance of international collaboration to overcome these barriers and accelerate clinical translation.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40291-025-00816-3.

Ageing of the haematopoietic system is characterized by phenotypic and functional impairments that are driven by alterations of haematopoietic stem cells and of the bone marrow niche. Haematopoietic stem cells are responsible for the production of all the different cell types that constitute the blood, and their maintenance and differentiation must be tightly regulated during the whole life of an organism. Exciting new data emphasize that central aspects of blood ageing, ranging from inflammageing and immunosenescence to clonal haematopoiesis, are mechanistically linked to dysfunction and ageing of other tissues, supporting a central role for the haematopoietic system in this context. Here we review some of the recent findings with a focus on ageing of the haematopoietic system and provide an overview of its role in driving healthspan and lifespan of the whole organism.

Anthracyclines are widely used in the treatment of many solid cancers, but their efficacy is limited by cardiotoxicity. As the number of pediatric cancer survivors continues to rise, there has been a concomitant increase in people living with anthracycline-induced cardiotoxicity. Accordingly, there is an ongoing need for new models to better understand the pathophysiological mechanisms of anthracycline-induced cardiac damage. Here we generated induced pluripotent stem cells (iPSCs) from two pediatric oncology patients with acute cardiotoxicity induced by anthracyclines and differentiated them to ventricular cardiomyocytes (hiPSC-CMs). Comparative analysis of these cells (CTX hiPSC-CMs) and control hiPSC-CMs revealed that the former were significantly more sensitive to cell injury and death from the anthracycline doxorubicin (DOX), as measured by viability analysis, cleaved caspase 3 expression, oxidative stress, genomic and mitochondrial damage and sarcomeric disorganization. The expression of several mRNAs involved in structural integrity and inflammatory response were also differentially affected by DOX. Functionally, optical mapping analysis revealed higher arrythmia complexity after DOX treatment in CTX iPSC-CMs. Finally, using a panel of previously identified microRNAs associated with cardioprotection, we identified lower levels of miR-22-3p, miR-30b-5p, miR-90b-3p and miR-4732-3p in CTX iPSC-CMs under basal conditions. Our study provides valuable phenotype information for cellular models of cardiotoxicity and highlights the significance of using patient-derived cardiomyocytes for studying the associated pathogenic mechanisms.

The main critical step in single-cell transcriptomics is sample preparation. Several methods have been developed to preserve cells after dissociation to uncouple sample handling from library preparation. Yet, the suitability of these methods depends on the cell types to be processed. In this project, we perform a systematic comparison of preservation methods for droplet-based single-cell RNA-seq on neural and glial cells derived from induced pluripotent stem cells. Our results show that while DMSO provides the highest cell quality in terms of RNA molecules and genes detected per cell, it strongly affects the cellular composition and induces the expression of stress and apoptosis genes. In contrast, methanol fixed samples display a cellular composition similar to fresh samples and provide a good cell quality and little expression biases. Taken together, our results show that methanol fixation is the method of choice for performing droplet-based single-cell transcriptomics experiments on neural cell populations.

<div>Abstract<p>Lymphangioleiomyomatosis (LAM) is a rare, low-grade metastasizing disease characterized by cystic lung destruction. LAM can exhibit extensive heterogeneity at the molecular, cellular, and tissue levels. However, the molecular similarities and differences among LAM cells and tissue, and their connection to cancer features are not fully understood. By integrating complementary gene and protein LAM signatures, and single-cell and bulk tissue transcriptome profiles, we show sources of disease heterogeneity, and how they correspond to cancer molecular portraits. Subsets of LAM diseased cells differ with respect to gene expression profiles related to hormones, metabolism, proliferation, and stemness. Phenotypic diseased cell differences are identified by evaluating lumican (LUM) proteoglycan and YB1 transcription factor expression in LAM lung lesions. The RUNX1 and IRF1 transcription factors are predicted to regulate LAM cell signatures, and both regulators are expressed in LAM lung lesions, with differences between spindle-like and epithelioid LAM cells. The cancer single-cell transcriptome profiles most similar to those of LAM cells include a breast cancer mesenchymal cell model and lines derived from pleural mesotheliomas. Heterogeneity is also found in LAM lung tissue, where it is mainly determined by immune system factors. Variable expression of the multifunctional innate immunity protein LCN2 is linked to disease heterogeneity. This protein is found to be more abundant in blood plasma from LAM patients than from healthy women.</p>Implications:<p>This study identifies LAM molecular and cellular features, master regulators, cancer similarities, and potential causes of disease heterogeneity.</p></div>

In 2020, SARS-CoV-2 and the COVID-19 pandemic had a huge impact on the access to and provision of ART treatments. Gradually, knowledge about the virus and its transmission has become available and has allowed ART activities to resume with certain restrictions. Still, questions on the impact of the virus on fertility and ART treatments remain.Regarding the possible consequences of COVID-19 in men, ACE2 and TMPRSS2, the receptors required for the viral penetration into cells, are highly expressed in the testis and the presence of SARS-CoV-2 has been demonstrated in the testicular tissue and the ejaculate in a small percentage of males with active and severe COVID-19 infection. Impairment of the sperm quality has been described during the acute and recovery phase of infection.In the female scenario, low levels of ACE2 have been reported in ovarian tissue and co-expression of ACE2 and TMPRSS2 has been demonstrated in oocytes, zygotes and blastocysts that are thus potentially susceptible to SARS-CoV-2 infection upon exposure to the virus. The endometrium has been shown to be at a low risk of infection. Although infrequent, vertical transmission of SARS-CoV-2 has been reported in cases of severe maternal infection.The effects of SARS-CoV-2 infection have been analysed in ART patients. Certain studies suggest that ovarian function might be altered and that IVF results could be poorer in patients that have recovered from COVID-19 while others show no evidence of compromised follicular function. The possible effects of vaccination in male and in female patients have also been explored. Neither the ovarian response nor the sperm quality is affected by the administration of COVID-19 vaccines, which are highly recommended in couples planning a pregnancy, either spontaneous or through ART.During the different waves of the COVID-19 pandemic, the ESHRE COVID-19 Working Group has produced recommendations and publications to guide patients and professionals in their journey through ART during these difficult times.

Liver diseases are major causes of morbidity and mortality. Dental pulp pluripotent-like stem cells (DPPSCs) are of a considerable promise in tissue engineering and regenerative medicine as a new source of tissue-specific cells; therefore, this study is aimed at demonstrating their ability to generate functional hepatocyte-like cells in vitro. Cells were differentiated on a collagen scaffold in serum-free media supplemented with growth factors and cytokines to recapitulate liver development. At day 5, the differentiated DPPSC cells expressed the endodermal markers FOXA1 and FOXA2. Then, the cells were derived into the hepatic lineage generating hepatocyte-like cells. In addition to the associated morphological changes, the cells expressed the hepatic genes HNF6 and AFP. The terminally differentiated hepatocyte-like cells expressed the liver functional proteins albumin and CYP3A4. In this study, we report an efficient serum-free protocol to differentiate DPPSCs into functional hepatocyte-like cells. Our approach promotes the use of DPPSCs as a new source of adult stem cells for prospective use in liver regenerative medicine.

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder that heavily burdens healthcare systems worldwide. There is a significant requirement to understand the still unknown molecular mechanisms underlying AD. Current evidence shows that two of the major features of AD are transcriptome dysregulation and altered function of RNA binding proteins (RBPs), both of which lead to changes in the expression of different RNA species, including microRNAs (miRNAs), circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and messenger RNAs (mRNAs). In this review, we will conduct a comprehensive overview of how RNA dynamics are altered in AD and how this leads to the differential expression of both short and long RNA species. We will describe how RBP expression and function are altered in AD and how this impacts the expression of different RNA species. Furthermore, we will also show how changes in the abundance of specific RNA species are linked to the pathology of AD.

We write in response to the editorial by Albin and Kordower,1 “A Failed Future,” which offers a perspective on the Multicentric Intracerebral Grafting in Huntington's Disease (MIG-HD) fetal cell transplantation study in Huntington's disease (HD).2 Although MIG-HD did not achieve a positive clinical outcome, Albin and Kordower's critique of that study provides critical points of interpretation that we believe incorrect. In particular, we reject their categorical rejection of cell therapy as a regenerative treatment option for HD on the basis of a single phase II study of fetal cell transplantation. Indeed, Albin and Kordower highlight the confounds potentially caused by protocol changes during MIG-HD that emphasize the exploratory nature of this trial. Cell therapy has advanced substantially since MIG-HD was initiated; we now have fuller understanding of the cellular phenotypes and interactions that go awry in HD and thus a clearer understanding of cell-based strategies that might be used in its treatment. We suggest that Albin and Kordower make unwarranted predictions of future failure—effectively “throwing out the baby with bath water”—based on an overly broad interpretation of MIG-HD, leading them to a conclusion that is neither justified nor cognizant of the current science and does a disservice to current work in the field. MIG-HD focused on achieving neural circuit reconstruction through transplanting striatal precursors isolated from fetal ganglionic eminence. It built on preclinical data and previous pilot human studies,3 which constituted proof of concept that transplants can improve function and that this may not require every element of pathology to be addressed, something borne out in Parkinson's disease transplant studies where pathology also exists outside the key central nervous system target of cell therapy.4 The limitations of fetal-derived donor cells stimulated research to derive candidate therapeutic progenitors (glial as well as neuronal5) from human pluripotent stem cells. Such cell products vary in their intended functions and therapeutic goals (eg, cell replacement, neuroprotection) with numerous reports of significant functional benefits (eg, Reidling and colleagues6). It is uninformative to lump these different products, targets, and therapeutic aims together and misleading to dismiss them all on the basis of a single phase II study initiated 2 decades ago. We believe a more productive approach is to formulate an honest, comprehensive appraisal of foreseeable challenges to develop a rational road map for moving forward. There should be due consideration of the limitations of MIG-HD and previous studies, leading to new perspectives on the design and implementation of clinical trials of cell therapies in HD (as reviewed in Bachoud-Lévi and colleagues7). Indeed, publication and informed analysis of such negative data are precisely how we may best ensure future success. To facilitate this, we established Stem Cells for HD (SC4HD; https://www.sc4hd.org/), a global consortium of experts working in various areas of cell therapy. The group invites external peer review and is developing evidence-based guidance documents for the establishment of best practices in the field. We believe that this is the right process by which to assess whether the complex, but potentially powerful, strategy of cell-based therapies can have a place in the treatment of HD.