This Issue's Introduction

The Scientific Foundations and Potential of Chemical Reprogramming

The Development and Advantages of Chemical Reprogramming Technology

The Prospects of Chemical Reprogramming in Regenerative Medicine

(Detailed application cases are included at the end!)

Summary

On August 16, 2024, the Future Science Prize announced its 2024 winners. Professor Deng Hongkui, Boya Chair Professor at Peking University and Leading Scientist at Changping Laboratory, was awarded the "Life Sciences Prize" for his groundbreaking work in pioneering chemical methods to reprogram somatic cells into pluripotent stem cells—revolutionizing the way we understand and manipulate cellular fate and state. Often referred to as a "magician" in his field, Professor Deng's research holds the potential to repair damaged, diseased, or aging cells, paving the way for future advancements that could push the boundaries of human health and longevity.

This revolutionary technique of chemical reprogramming, with its unique scientific appeal and immense application potential, has ushered in unprecedented promise for the field of regenerative medicine. Not only does this technology offer us a fresh perspective on deeply understanding cellular plasticity, but it also opens up entirely new avenues for treating diseases that have long remained challenging for conventional medicine!

On March 20, 2023, Hongkui Deng and Jinlin Wang from Peking University co-authored a research paper titled "Highly efficient and rapid generation of human pluripotent stem cells by chemical reprogramming," which was published online in Cell Stem Cell (IF=25). The study demonstrated that chemical reprogramming can efficiently and rapidly generate human pluripotent stem cells.

(Professor Deng Hongkui)

 

1. NEWS

The Scientific Foundations and Potential of Chemical Reprogramming

As cold gives way to heat and the seasons shift, all things follow their natural rhythms—so too does the growth and development of cells. Beginning with the fertilized egg, cells gradually divide and differentiate, maturing into specialized, fully functional somatic cells that take on distinct roles. These cells then undergo processes like proliferation, aging, and eventually apoptosis. Once upon a time, the scientific community believed that this "programmed" fate of cells was irreversible. Highly specialized, mature somatic cells were thought to be stable and incapable of bypassing the "epigenetic barrier" to transdifferentiate into other cell types—after all, maintaining the normal functions of tissues across the body is critical for overall health.

However, as life sciences and regenerative medicine continue to advance, this view has come under challenge. In the 1960s, several scholars successively discovered that nuclear transplantation of mature cells can reprogram them into cells with characteristics similar to those of fertilized eggs, effectively restoring their "new life." Since then, cellular plasticity has become a key focus of intensive research in the academic community.

(On the left is British scientist John Gurdon, and on the right is Japanese scientist Shinya Yamanaka, awarded for "discovering that mature cells can be reprogrammed into pluripotency.")

Chemical reprogramming is a technique that uses small chemical molecules to induce somatic cells to revert into pluripotent stem cells, possessing significant scientific foundations and vast application potential. This technology not only advances our understanding of cell fate determination and transformation mechanisms but also opens up new possibilities for regenerative medicine in treating severe diseases.

Its scientific foundation lies in using small chemical molecules to mimic external signals, thereby driving cells to undergo fate transitions in a stepwise manner. Compared with traditional transgenic reprogramming techniques, this approach offers several advantages, including superior controllability, no genomic integration, and reversible effects. The research team led by Deng Hongkui has demonstrated that the chemical reprogramming process is a highly organized, stage-by-stage procedure, during which cells progress through distinct intermediate states before ultimately reaching a pluripotent state.

 

The Potential and Applications of Chemical Reprogramming Technology

1. Regenerative Medicine: CiPS cells possess the remarkable ability to differentiate into various cell types, offering a novel strategy for tissue repair and organ regeneration. They particularly show immense potential in treating conditions such as diabetes, Parkinson’s disease, and heart diseases.

 

2. Cell Therapy: Chemical reprogramming technology can be used to generate patient-specific stem cells, thereby avoiding immune rejection issues and paving the way for personalized medicine.

 

3. Drug Screening and Disease Modeling: CiPS cells can be used to establish disease models, conduct drug screening and toxicity tests, and accelerate the development of new pharmaceuticals.

 

4. Anti-Aging Research: Chemical reprogramming may help reverse age-related cellular changes, paving the way for the development of novel anti-aging therapies.

 

5. Basic Research: Chemical reprogramming provides new tools and models for studying cell fate determination, cellular plasticity, and developmental biology.

Simply put, the potential of chemical reprogramming lies in its multifaceted applications, including significant value in areas such as cell therapy, drug screening, and disease modeling. For instance, Hongkui Deng's team successfully used human CiPS cells to efficiently generate pancreatic islet cells, and they have already demonstrated the safety and efficacy of this approach in treating diabetes using large-animal models. Moreover, chemical reprogramming technology holds tremendous promise for advancing tissue and organ regeneration as well as combating aging!

Technical Challenges and Future Development:

 

1. Enhancing Efficiency and Speed: Although chemical reprogramming has made progress, there is still a need to improve its induction efficiency and shorten the reprogramming cycle to meet the demands of clinical applications.

 

2. Delving into Molecular Mechanisms: Further investigate the molecular mechanisms underlying chemical reprogramming, particularly how small molecules influence intracellular signaling networks and epigenetic states.

 

3. Safety Assessment: Ensure the safety of the compounds used during chemical reprogramming, minimizing potential side effects and carcinogenic risks.

 

4. Clinical Applications: Promote the translation of chemical reprogramming technology into clinical practice, including developing standardized reprogramming protocols and evaluating long-term outcomes.

 

5. Integration of New Technologies: By combining cutting-edge technologies such as artificial intelligence and multi-omics analysis, we aim to optimize the chemical reprogramming process, enabling more precise control over cellular fate.

Overall, the research achievements of Deng Hongkui's team have laid a solid foundation for the field of chemical reprogramming, continuously driving the advancement and application of this technology. As our understanding of the mechanisms underlying chemical reprogramming deepens, we can look forward to even greater breakthroughs in areas such as regenerative medicine and cell therapy in the future.

 

Two NEWS

The Development and Advantages of Chemical Reprogramming Technology

Chemical reprogramming technology is an innovative biotechnology approach that uses specific small chemical molecules to induce somatic cells to revert into pluripotent stem cells (CiPS cells). This technology first emerged in 2013, when Hongkui Deng’s team at Peking University demonstrated for the first time that mouse somatic cells could be chemically reprogrammed into pluripotent stem cells using small chemical molecules.

Subsequently, in 2022, the team achieved a breakthrough by successfully converting human adult cells into pluripotent stem cells using chemical methods, paving the way for new advancements in regenerative medicine and cell therapy.

Subsequently, the team and other researchers have continuously refined the chemical reprogramming technology, improving its induction efficiency, shortening the reprogramming cycle, and exploring various small-molecule combinations and underlying mechanisms. Today, chemical reprogramming technology has been applied to a wide range of cell types and species, with promising applications in areas such as disease model development, drug screening, and cell-based therapies.

 

Advantages of Chemical Reprogramming Technology

1. Ease of Operation: Chemical reprogramming utilizes small-molecule compounds, making the process simple and easy to standardize. Compared to traditional methods like genetic engineering or somatic cell nuclear transfer, it requires a lower technical barrier.

 

2. Spatiotemporal Controllability: The effects of small-molecule compounds can be precisely regulated, both in terms of intensity and duration, paving the way for accurate manipulation of cellular fate.

 

3. Non-integrative Nature: Chemical reprogramming does not involve genome integration, thereby avoiding potential genomic instability and safety concerns caused by the insertion of exogenous genes.

 

4. Reversibility: The action of small molecules is reversible, allowing specific cellular states to be activated or inhibited as needed, thereby providing flexibility for the dynamic regulation of cell fate.

 

5. Deepening the Understanding of Molecular Mechanisms: Research on chemical reprogramming helps to gain a deeper insight into the molecular mechanisms underlying cell fate transitions, including transcriptional regulation, epigenetic modifications, and metabolic pathways.

 

6. Wide-ranging application prospects: Chemical reprogramming technology holds vast potential for applications in regenerative medicine, cell therapy, drug screening, and the establishment of disease models.

 

7. Fewer Ethical Concerns: Compared to methods that use embryonic stem cells or involve animal-derived materials, chemical reprogramming techniques avoid ethical controversies and the risk of cross-species transmission.

 

8. Promoting Tissue Regeneration and Combating Aging: Chemical reprogramming technology holds great promise in advancing tissue and organ regeneration, as well as paving the way for anti-aging therapies.

 

9. Utilization of Natural Products: Many natural product small molecules have demonstrated significant roles in chemical reprogramming, and the diversity and complexity of these natural products provide a rich resource for discovering new, potent small molecules.

In summary, as chemical reprogramming technology continues to advance and optimize, it is expected to play an increasingly important role in future biomedical research and clinical applications.

 

Three NEWS

The Prospects of Chemical Reprogramming in Regenerative Medicine

Chemical reprogramming technology holds revolutionary potential in regenerative medicine. By converting human cells into pluripotent stem cells, it offers entirely new strategies and approaches for cell therapy, tissue and organ regeneration, drug screening, disease modeling, and anti-aging research. With its advantages of simplicity, high safety, ease of standardization, and precise regulation, this technology is poised to drive the advancement of regenerative medicine, accelerate the discovery and implementation of innovative therapies, and further solidify China's leadership in the life sciences.

 

The Application of Chemical Reprogramming Technology in Regenerative Medicine

1. Cell Therapy: Chemical reprogramming technology can transform human cells into pluripotent stem cells, which have the remarkable ability to differentiate into various functional cell types, offering a new source for cell-based therapies.

2. Organ and Tissue Regeneration: Chemical reprogramming not only generates multipotent stem cells but also enables in vivo, in situ induction of specific cell type conversions—such as transforming astrocytes into neurons or fibroblasts into cardiomyocytes—thereby promoting the regeneration of tissues and organs.

3. Drug Screening and Toxicity Testing: Chemical reprogramming technology can be used to establish disease models, enabling drug screening and toxicity testing using specifically differentiated cell types, thereby accelerating the development of new pharmaceuticals.

4. Anti-Aging Research: Chemical reprogramming, during the process of reprogramming somatic cells into a pluripotent state, can erase age-related epigenetic markers, offering new insights and approaches for developing anti-aging therapies.

5. Establishing Disease Models: By leveraging chemical reprogramming technology, it is possible to capture stem cell types at various developmental stages in vitro, enabling the creation of both primed and lineage-extended pluripotent stem cell culture systems—providing crucial models for disease research.

6. Long-term Maintenance of Functional Cells: Chemical small molecules can also enable the long-term in vitro maintenance of functional cells such as primary liver cells, hematopoietic stem cells, and intestinal organoids, which is of great significance for studying cellular functions and developing novel therapeutic strategies.

7. Driving the Life Sciences Center Toward China: The research achievements of Deng Hongkui’s team are not only scientifically innovative but have also played a crucial role in positioning China as a global leader in the field of life sciences.

Case studies of chemically reprogramming technology:

 

1. Chemically Induced Pluripotent Stem Cells (CIPS):

The research team successfully induced mouse somatic cells to transform into pluripotent stem cells—known as CIPS—by screening a specific combination of chemical small molecules.

These cells not only have the ability to differentiate into multiple cell types, but when injected into early mouse embryos, they can generate chimeric mice—with 100% survival rate observed throughout the study period and no tumor formation—demonstrating that the chemically induced reprogramming method is highly safe.

 

2. In vitro preparation of liver cells:

The team has developed an in vitro culture system that can differentiate pluripotent stem cells into functional liver cells. Under the influence of specific combinations of small chemical molecules, these cells maintain their functionality over the long term, making them ideal for drug screening, studies on viral infections, and even clinical applications.

In particular, the team collaborated with Gulou Hospital to use these externally prepared liver cells for treating severe liver failure. By employing a bioreactor system to purify the patients' blood outside the body, they successfully improved the patients' liver function.

 

3. In vivo in situ reprogramming:

Researchers have discovered a set of small chemical molecules that can directly convert astrocytes into functional neurons within the mouse brain.

These in situ-generated neurons are capable of firing action potentials and forming functional networks with surrounding nerve cells, offering a new strategy for treating neurodegenerative diseases.

 

4. Clearance of senescent cells:

The research team collaborated with Peking University to design a prodrug that leverages the characteristic of galactosidase—a enzyme highly expressed in senescent cells. By using chemically modified small molecules bearing galactose groups, the prodrug is enzymatically cleaved specifically within senescent cells, transforming into a toxic molecule that triggers apoptosis in these aged cells.

This selective method of eliminating senescent cells helps reduce systemic inflammation levels and enhances the repair and regenerative capacity of tissues and organs.

 

5. Treatment of COVID-19-infected elderly patients:

Researchers have found that eliminating senescent cells can reduce the rate of severe illness among elderly COVID-19 patients. Senescent cells secrete inflammatory factors that elevate the body's inflammation levels, thereby increasing the risk of severe outcomes following COVID-19 infection.

By using the aforementioned chemical small molecules to eliminate senescent cells, it is possible to reduce the severity of lung lesions and lower levels of inflammatory factors in the body, thereby alleviating symptoms and promoting regenerative repair.

 

6. Human-monkey chimeric embryo:

Using EPS cells— a novel type of pluripotent stem cell—the research team collaborated with laboratories both domestically and internationally, injecting human EPS cells into early-stage monkey embryos and successfully generating human-monkey chimeric embryos.

This work not only demonstrates the remarkable chimeric potential of EPS cells, but also lays a crucial scientific foundation for the future development of human organs within animal bodies.

The advancement of chemical reprogramming technology, particularly driven by Deng Hongkui's team, has already surpassed the limitations of traditional iPS technology, demonstrating greater safety, simplicity, and ease of standardization—qualities that lay a solid foundation for the translational applications of regenerative medicine. Looking ahead, as the technology continues to evolve and improve, chemical reprogramming is poised to play an even more pivotal role in the future of regenerative medicine.

 

Four NEWS

Summary

Overall, chemical reprogramming technology has successfully achieved cell fate conversion through precise combinations of small chemical molecules, opening up a new frontier in regenerative medicine. From culturing functional liver cells with therapeutic potential in vitro, to directly converting astrocytes into neurons within the body, to selectively eliminating senescent cells to reduce the severity rate among elderly COVID-19 patients, and even to generating human-monkey chimeric embryos—this innovative approach is pushing the boundaries of cellular manipulation and medical innovation.

These cases not only demonstrate the advantages of chemical reprogramming in terms of safety and efficacy, but also highlight its immense potential for disease treatment and health promotion. As this technology continues to advance and undergo deeper research, we can confidently expect that chemical reprogramming will bring even more innovative solutions to human health!