Scientific Origin of CiPSC

Pluripotent Stem Cells (PSCs) are cells that can self-renew and differentiate into various human cells and tissues, making them essential for cell therapy, drug screening, and disease modeling. They are the most critical "seed cells" in regenerative medicine.

In animals like salamanders, cells exhibit strong regenerative potential, activating precise genetic programs to repair damaged tissue. In mammals, however, PSCs exist only briefly during early embryonic development before maturing into highly specialized cells that support complex life functions and tissue stability. While beneficial for overall stability, this specialization limits the capacity for self-repair after injury.

If adult cells, which have undergone significant differentiation, could be reprogrammed to regain a pluripotent state similar to early embryonic development, it would enable the production of human organs, tissues, and cells to address various issues related to aging, disease, injury, or genetic defects. Thus, reversing the biological clock of cells is one of the most critical challenges in regenerative medicine.

The birth of the cloned sheep Dolly in 1996 and the first establishment of human embryonic stem cell lines in 1998 shocked the world. Dolly's birth demonstrated that highly differentiated somatic cells in mammals could be reverted to an early embryonic state, gaining the ability to develop into a complete animal. The isolation of human stem cells also initiated research into human pluripotent stem cells. This pivotal moment led Professor Hongkui Deng, the scientific founder of BeiCell Therapeutics, who was then studying immunology, to shift his focus to the field of regenerative medicine.

In 2006, Shinya Yamanaka and his team discovered that forcing the expression of specific transcription factors could convert fibroblasts into induced pluripotent stem cells (iPSCs), marking a new era in regenerative medicine. However, the use of transcription factor-based reprogramming faces limitations, such as potential random transgene integrations and the expression of oncogenes.

To overcome these challenges, Hongkui Deng pioneered an approach of using small molecules to convert fibroblasts into iPSCs (termed CiPSCs, for chemically induced pluripotent stem cells). He showed that CiPSCs are germline-competent and can be used to successfully produce mice (2013), and revealed the underlying molecular pathways leading to CiPSC generation (2015, 2018).

However, the complex characteristics and regulatory mechanisms of human adult cells present significant epigenetic barriers, severely limiting the potential to induce plasticity in these cells. Since 2013, despite substantial efforts inspired by work on mouse chemical reprogramming, the challenge of chemically reprogramming human adult cells remained unsolved, leading to the belief that epigenetic barriers in human cells are extremely stringent.

This belief persisted until 2022, when Deng's team published a paper in Nature, successfully generating human CiPSCs and demonstrating that human CiPSC-derived islets can ameliorate diabetes in non-human primates, showcasing the great clinical potential of hCiPSCs (2022a, 2022b, 2023).

Deng's seminal and transformative work has opened a new route for cellular reprogramming, with broad and long-term impact on stem cell research and regenerative medicine.

Hongkui Deng, born in 1963 in Beijing, China. PhD: 1995 from University of California, Los Angeles. Current position: Boya Chair Professor of Peking University and Leading Scientist of Changping Laboratory, China.

References:

Hou et al. (2013) Science 341:651

Zhao et al. (2015) Cell 163:1678

Zhao et al. (2018) Cell Stem Cell 23:31

Guan et al. (2022a) Nature 605:325

Liuyang et al (2023) Cell Stem Cell 30:450

Du et al. (2022) Nature Medicine 28:272