International journal of stem cells最新文献

A rare disease is generally defined as a medical condition that affects a small proportion of the population, though specific thresholds vary across countries. Despite regional differences, these definitions consistently reflect the low prevalence of such conditions, the limited availability of effective treatments, and the pressing need for targeted research and regulatory support. As a result of their rarity and low commercial potential, rare diseases have historically represented an area of market failure, where investment and research have been limited and often neglected. However, since the 1990s, each country has guaranteed continuous support to research and development projects to promote the advancements of rare disease treatments, achieving a growth rate greater than that of the entire pharmaceutical industry. In this review, we examine the status of orphan drug development using an advanced therapy medicinal product (ATMP) approach in the growing rare disease market, with a particular focus on cell therapies and gene therapies, which constitute the most actively developed and clinically applied categories within ATMPs. We also explore strategic approaches through which the orphan drug industry can utilize ATMPs, especially these two modalities, to enhance its competitiveness.

Bronchopulmonary dysplasia (BPD), characterized by impaired alveolarization and dysregulated vascularization, is a severe health burden for neonates worldwide. Hyperoxia induced acute lung injury is a major contributor to the progression and deterioration of BPD. An increasing number of animal studies have revealed that human umbilical cord blood derived mononuclear cells (hUCB-MNCs) infusion significantly attenuated the hyperoxia-induced acute lung injury through regeneration capacity. Currently, clinical application requires determination of the optimal dose and adjustment to good manufacturing practices. In this work, we comprehensively investigated the optimal dose of hUCB-MNCs in alleviating hyperoxia-induced lung injury in neonatal C57BL6/J mice. Mice with hyperoxia exposure were implanted with low (3×10⁴ cells/kg, Dl), middle (3×10⁵ cells/kg, Dm) and high (3×10⁶ cells/kg, Dh) dose of hUCB-MNCs at postnatal day 7. Three weeks after graft, characteristics exhibited in lungs including morphology, function and cytokine expression were thoroughly analyzed. Implantation of hUCB-MNCs sharply reverted the impaired lung architecture induced by hyperoxia exposure dose dependently as evidenced by indicated parameters. Attenuated expression of IL-1β concomitant with enhanced expression of IL-10 and IL-2 were shown in Dh inoculated groups, where Dl and Dm failed to restore the level of IL-10, IL-1β and IL-2. Significantly re-escalated marker of angiogenic marker VEGFA, CD31 in lung tissue were uniquely observed in Dh group. Mechanistically, our study revealed the appropriate dose of intravenous infusion of hUCB-MNCs in alleviating hyperoxia-induced lung injury through modulating reactive oxygen species response in neonatal mice. Therefore, a tight control of hUCB-MNCs density or levels of CB-MNC related products is of great significance.

There is mounting epidemiologic and experimental evidence of the harmful effects of exposure to fine particulate matter (PM2.5) on human lung health. However, the current utilization of in vitro two-dimensional (2D) cell culture and in vivo animal models falls short in accurately recapitulating the complexity, functions, and development of the human lung. Recently, technologies for creating 3D biomimetic lung organoids from human tissue and pluripotent stem cells that mimic the structure and function of human organs have been rapidly developed. Human lung organoids are currently being applied in various studies such as disease modeling, drug efficacy testing, and regenerative medicine. In the field of environmental toxicology, human lung organoids offer a promising solution for more accurately assessing the health impacts of exposure to PM2.5 and to the limitations posed by 2D cultures and animal models. In this review, we summarize the effects of PM2.5 exposure on human lung and other organoids, as well as the molecular and genetic impacts of such exposure using human organoids. Furthermore, the development of lung-on-a-chip technology to mimic the microenvironment and its utilization for evaluating the pulmotoxicity of PM2.5 exposure are discussed.

Human pluripotent stem cells (hPSCs) can be used to investigate hematopoietic development and have the potential to advance cell-based therapies and to facilitate developmental biology studies. However, efficient ex vivo differentiation into hematopoietic lineages, including red blood cells (RBCs) of the erythroid lineage and immune cells such as macrophages of the myeloid lineage, is hampered by the need for precise temporal regulation of cytokines and growth factors. In this study, we developed an optimized protocol for hematopoietic lineage specification from hPSCs by fine-tuning the temporal dynamics of cytokine and growth factor applications. Prolonged mesodermal specification in the absence of hemogenic cytokines significantly enhanced the generation of hematopoietic progenitors (CD34^＋CD45^＋) with robust functional potential. Early administration of interleukin (IL)-3 during hematopoietic specification promoted progenitor expansion and maturation. Supplementation of bone morphogenetic protein 4 at the hematopoietic maturation stage enhanced the differentiation efficiency and preferentially drove myeloid lineage commitment toward macrophages at the expense of erythroid differentiation. The timing of erythropoietin administration was important in erythroid lineage commitment, and delayed treatment (day 10) enhanced erythroblast expansion and RBC production. By contrast, the timing of IL-6, GM-CSF, and M-CSF exposure did not significantly affect macrophage differentiation efficiency, suggesting that myeloid lineage specification follows a default pathway under optimized differentiation conditions. These findings suggest a refined, time-controlled strategy for directing hematopoietic differentiation from hPSCs, and provide insight into therapeutic blood cell production, regenerative medicine, and ex vivo modeling of hematopoietic disorders.

Phenylketonuria (PKU), an autosomal recessive genetic disorder, has been documented to exhibit over 950 distinct mutations. This condition primarily affects the metabolism of phenylalanine, which is affected by a deficiency in the hepatic enzyme phenylalanine hydroxylase. The optimal treatment for PKU disease remains to be determined, necessitating further research. The severity of the disease and the most effective treatment method vary depending on the specific mutation, which necessitates the development of personalized treatment strategies. In this study, we successfully established induced pluripotent stem cell (iPSC) lines from the blood of a PKU patient with the R243Q mutation via Sendai virus-based reprogramming (R243Q-iPSCs). The established R243Q-iPSCs exhibited characteristics of pluripotency, as confirmed through quantitative reverse transcription polymerase chain reaction, western blot, immunocytochemistry, and karyotype analysis. Furthermore, these iPSCs not only successfully differentiated into hepatocytes but also exhibited a complete PKU disease phenotype. These results provide a valuable foundation for PKU disease research, including physiological studies of PKU, gene therapy, drug screening, and the development of platforms for novel cell therapy approaches.

Nanog is a key transcription factor that regulates the self-renewal and pluripotency of embryonic stem cells (ESCs). Although Kap1 has been demonstrated to regulate the stability of stemness factors, including Oct4 and Lin28A, its role in regulating Nanog protein stability in ESCs remains unexplored. In the present study, we examined the interaction between Kap1 and Nanog and its role in stabilizing the Nanog protein. Immunoprecipitation assays revealed that Nanog specifically interacted with the coiled-coil domain of Kap1. Kap1 overexpression increased the stability of the Nanog protein by inhibiting its ubiquitination and proteasomal degradation, whereas Kap1 silencing accelerated Nanog degradation. Furthermore, Kap1 overexpression inhibits Nanog degradation by interfering with the binding of Nanog to Fbxw8, an E3 ubiquitin ligase that promotes Nanog degradation via a proteasome-dependent process. These results indicate that Kap1 acts as a key regulator to preserve ESC properties by modulating the protein stability of stemness factors, including Oct4, Lin28A, and Nanog.

Transcription factor CP2-like protein 1 (Tfcp2l1), a naïve pluripotency transcription factor, is expressed in both early embryonic and adult tissues, where it enforces pluripotency of embryonic stem cells (ESCs) and stemness features of cancer cells, respectively. However, the detailed molecular pathways by which Tfcp2l1 is regulated in early embryonic development and cancer cells remain unknown. Here, we identified the pseudophosphatase dual specificity phosphatase 27 (Dusp27), also known as serine/threonine/tyrosine-interacting like-2, as a novel Tfcp2l1-interacting protein through a sterile alpha motif-like domain in the C-terminus of Tfcp2l1 in murine ESCs. The interaction between Dusp27 and Tfcp2l1 was dependent on the cell cycle status and increased during mitosis. Expression of Dusp27 was upregulated during naïve pluripotency and repressed during spontaneous differentiation of murine ESCs. Ectopic expression of Dusp27 enhanced the transcriptional activity of Tfcp2l1 and promoted features associated with the naïve pluripotent state, while suppressing meso-endodermal lineage differentiation. The present study demonstrates that Dusp27 is a novel positive regulator of Tfcp2l1 through a physical interaction and thereby fine-tunes the pluripotency status and meso-endodermal differentiation of murine ESCs.

Stem cell-derived embryo models (SCDEMs) create opportunities to investigate the morphological dynamics and underlying mechanisms of embryonic development, implantation, and post-implantation progression by recapitulating pre-and peri-implantation stages in vitro-an area that conventional in vivoapproaches struggle to investigate. This review provides a comprehensive overview of SCDEMs, detailing the methodologies used to generate synthetic embryos and the diverse types of stem cells employed. Furthermore, we describe how closely these models recapitulate key developmental processes pre- and post-implantation, thereby establishing their value as a platform for studying early mammalian embryogenesis. In addition, we suggest that synthetic embryos are valuable tools for studying environmental toxicity, yet ethical and technical constraints limit systematic in vivo investigations. We evaluate the strengths and limitations of these models in embryotoxicity studies and highlight future research strategies. SCDEMs are expected to significantly advance the broader field of early mammalian developmental biology, with impacts extending well beyond their use in embryotoxicology.

The advent of medical advances has resulted in the development of an array of treatments aimed at restoring damaged organs in humans. However, when chemical treatments, such as drug therapies, are constrained, organ transplantation may ultimately emerge as the sole viable solution. Nevertheless, despite the continually increasing demand for organ donations, the actual number of donated organs remains insufficient to meet this demand. Recently, a variety of organoids have been generated using stem cells and have been demonstrated to exhibit functionality comparable to that of native organs. This indicates that organoids may be a viable option for use in organ transplantation. However, while numerous recent publications have documented the regenerative effects of diverse organoid types when implanted into damaged regions, significant technical and ethical considerations must be addressed before organoids can be utilized as a replacement for human organs. This review presents an overview of experimental endeavors in regenerative therapies through organoid transplantation, while also addressing the challenges that must be overcome to enhance the feasibility of organoid use as a surrogate organ. As organoid technology continues to advance, organoids may eventually become a widely utilized surrogate source for organ replacement in clinical settings.