Introduction

Human pluripotent stem cells (hPSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), hold immense promise for regenerative medicine, disease modeling, and developmental biology research. Over the past five years, significant strides have been made in refining hPSC derivation, improving differentiation protocols, and leveraging hPSCs to create complex in vitro models that recapitulate human development and disease. This mini-review highlights key advancements in these areas, focusing on modeling early development, strategies for promoting cellular maturation, and therapeutic applications of hPSC-derived cells.

Modeling Early Human Development with hPSCs

A major area of advancement involves using hPSCs to model early human development, particularly the blastocyst and post-implantation stages. Jun Wu's group has demonstrated the generation of blastocyst-like structures from hPSCs, providing a valuable tool for studying early human embryogenesis (Leqian Yu et al., 2020, Nature; Leqian Yu et al., 2021, Nature). Complementing this work, José M. Polo's laboratory developed "iBlastoids" by reprogramming fibroblasts, offering an alternative approach to model the human blastocyst (Xiaodong Liu et al., 2020, Nature; Xiaodong Liu et al., 2021, Nature). Nicolas Rivron's group further refined this area by creating human blastoids that model blastocyst development and implantation (Harunobu Kagawa et al., 2021, Nature).

The ability to capture and characterize naive pluripotency has also been a focus. Austin Smith's team, in collaboration with Ge Guo and Masaki Kinoshita, has made significant contributions to the capture of mouse and human stem cells with features of formative pluripotency (Masaki Kinoshita et al., 2020, Cell stem cell; Ge Guo et al., 2020, Cell stem cell; Ge Guo et al., 2021, Cell stem cell; Ayaka Yanagida et al., 2021, Cell stem cell). Md. Abdul Mazid's research group has even rolled back human pluripotent stem cells to an eight-cell embryo-like stage (Md. Abdul Mazid et al., 2022, Nature).

More recently, researchers have pushed the boundaries further by generating models of the post-implantation human embryo. Jacob H. Hanna's lab has developed post-gastrulation synthetic embryos from mouse naive ESCs (Shadi Tarazi et al., 2022, Cell) and complete human day 14 post-implantation embryo models from naive ES cells (Bernardo Oldak et al., 2023, Nature). Similarly, Magdalena Zernicka‐Goetz's group has created a pluripotent stem cell-derived model of the post-implantation human embryo (Bailey A. T. Weatherbee et al., 2023, Nature). Berna Sözen's team has shown self-patterning of human stem cells into post-implantation lineages (Monique Pedroza et al., 2023, Nature). These models offer unprecedented opportunities to study early human development in vitro, although ethical considerations remain paramount.

Enhancing hPSC-Derived Cell Maturation and Function

A persistent challenge in the field is the generation of fully mature and functional cells from hPSCs. Researchers have explored various strategies to address this limitation. Mark Mercola's group has demonstrated that metabolic maturation media can improve the physiological function of human iPSC-derived cardiomyocytes (Dries Feyen et al., 2020, Cell Reports). Gordon Keller's lab has focused on generating mature compact ventricular cardiomyocytes from hPSCs (Shunsuke Funakoshi et al., 2021, Nature Communications). Michael A. Laflamme's team showed that in vitro matured hPSC-derived cardiomyocytes form grafts with enhanced structure and function in injured hearts (Wahiba Dhahri et al., 2022, Circulation). Timo Otonkoski's group has made progress in achieving functional, metabolic, and transcriptional maturation of human pancreatic islets derived from stem cells (Diego Balboa et al., 2021, Nature Biotechnology; Diego Balboa et al., 2022, Nature Biotechnology). Lorenz Studer's laboratory has shown that combined small-molecule treatment accelerates maturation of human pluripotent stem cell-derived neurons (Emiliano Hergenreder et al., 2024, Nature Biotechnology). Gabriele Ciceri's research group has identified an epigenetic barrier that sets the timing of human neuronal maturation (Gabriele Ciceri et al., 2023, Nature; Gabriele Ciceri et al., 2024, Nature).

Therapeutic Applications and Disease Modeling

The ultimate goal of much hPSC research is to develop cell-based therapies and improved disease models. Kwang‐Soo Kim's group has explored personalized iPSC-derived dopamine progenitor cells for Parkinson’s disease (Jeffrey S. Schweitzer et al., 2020, New England Journal of Medicine). Jun Takahashi's team has conducted pre-clinical studies of iPSC-derived dopaminergic progenitor cells for Parkinson’s disease (Daisuke Doi et al., 2020, Nature Communications). Shin Kaneko's lab has developed a clinically applicable and scalable method to regenerate T-cells from iPSCs for off-the-shelf T-cell immunotherapy (Shoichi Iriguchi et al., 2021, Nature Communications). Hongkui Deng's group has demonstrated that human pluripotent stem-cell-derived islets ameliorate diabetes in non-human primates (Yuanyuan Du et al., 2022, Nature Medicine). Agnete Kirkeby and Malin Parmar's teams have reported on the preclinical quality, safety, and efficacy of a human embryonic stem cell-derived product for the treatment of Parkinson’s disease (Agnete Kirkeby et al., 2023, Cell stem cell). Noriyuki Tsumaki's lab has shown engraftment of allogeneic iPS cell-derived cartilage organoid in a primate model of articular cartilage defect (Kengo Abe et al., 2023, Nature Communications). Keiichi Fukuda's group has achieved regeneration of nonhuman primate hearts with human induced pluripotent stem cell–derived cardiac spheroids (Hideki Kobayashi et al., 2024, Circulation). Shigeru Miyagawa's team has reported a case of transplantation of human induced pluripotent stem cell-derived cardiomyocyte patches for ischemic cardiomyopathy (Shigeru Miyagawa et al., 2022, Front. cardiovasc. med.).

Furthermore, hPSCs are increasingly used to generate organoids for disease modeling. Lika Drakhlis's group has developed human heart-forming organoids that recapitulate early heart and foregut development (Lika Drakhlis et al., 2020, Nature Biotechnology; Lika Drakhlis et al., 2021, Nature Biotechnology). Aitor Aguirre's lab has created self-assembling human heart organoids for modeling cardiac development and congenital heart disease (Yonatan R. Lewis‐Israeli et al., 2021, Nature Communications). Daniel H. Geschwind's group has shown long-term maturation of human cortical organoids that matches key early postnatal transitions (Aaron Gordon et al., 2021, Nature Neuroscience). Yiling Hong's team has developed microglia-containing cerebral organoids derived from induced pluripotent stem cells for the study of neurological diseases (Yiling Hong et al., 2023, iScience). Chong Li and Juergen A. Knoblich's laboratories have used single-cell brain organoid screening to identify developmental defects in autism (Chong Li et al., 2023, Nature). Jason S. Meyer's group has developed a highly reproducible and efficient method for retinal organoid differentiation from human pluripotent stem cells (Jade Harkin et al., 2024, Proceedings of the National Academy of Sciences). Sergiu P. Paşca's team has used antisense oligonucleotide therapeutic approach for Timothy syndrome (Xiaoyu Chen et al., 2024, Nature). Dawood Darbar and Salman R. Khetani's laboratories have engineered cocultures of iPSC-derived atrial cardiomyocytes and atrial fibroblasts for modeling atrial fibrillation (Grace E. Brown et al., 2024, Science Advances). Nurcan Üçeyler's team has developed a human-derived neuronal in vitro disease model and pilot data for small fibre neuropathy in Fabry disease (Thomas Klein et al., 2024, Brain commun.).

Conclusion

The past five years have witnessed remarkable progress in hPSC research. From creating sophisticated models of early human development to developing refined differentiation protocols and exploring therapeutic applications, the field continues to advance rapidly. While challenges remain, particularly in achieving complete cellular maturation and ensuring the safety and efficacy of cell-based therapies, the ongoing research promises to unlock the full potential of hPSCs for understanding human biology and treating disease.

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