Rachel Lim ‘29
In October 1958, an accident at a nuclear research institute near Belgrade exposed five physicists to dangerously high levels of radiation. A month later, the physicists were flown to Paris to be treated by immunologist Dr. Georges Mathé, who turned to a strategy never used before in humans: replacing damaged tissues with bone marrow from healthy donors. Suffering from hair loss and infections after radiation destroyed their dividing cells and suppressed their immune systems, the Yugoslavian men were led to believe they were receiving blood transfusions to calm them for the procedure, which would be highly unethical by today’s standards. On November 11, within a week of the transplant, four of the five men began recovering. Only the fifth man, who experienced the highest level of radiation exposure, passed away.
Dr. Mathé’s case demonstrated that allogeneic cellular transplantation – in which transplanted cells originate from a donor rather than oneself – was possible. This breakthrough helped spur the emergence of modern regenerative medicine, a field based on the idea that an individual’s cells and tissues can be restored and replaced to treat injuries and diseases.
Nearly 70 years after Dr. Mathé’s success, stem cell transplantation is used to treat leukemias. Bone marrow is usually received from a sibling or from a stranger whose cells have a low chance of being rejected by the recipient’s immune system, a compatibility determined by HLA (human leukocyte antigen) typing. Once transplanted into the bone marrow, stem cells can produce new blood cells in the recipient’s body, restoring healthy blood production in patients who have undergone high-dose chemotherapy or radiation.
How can stem cells produce new blood cells? The answer lies in their distinct ability to regenerate and differentiate into specialized cells. Unlike muscle cells, blood cells, or nerve cells, stem cells replicate many times. They can divide into two stem cells, a stem cell and one more differentiated cell, or two more differentiated cells. Their transformations into specific cell types are driven by factors secreted by other cells, physical contact with neighboring cells, and certain molecules in the microenvironment. Scientists have been able to characterize the various chemical environments required for the differentiation of stem cells into specific cell types such as neurons, insulin-producing pancreatic cells, or cardiac cells.
However, not all stem cells are created equal. Pluripotent stem cells can differentiate into any cell type in the body, while multipotent adult stem cells (also referred to as somatic stem cells) can differentiate into one or several specific cell types limited to their tissue of origin.
Embryonic stem cells (ESCs) were first discovered in mice in 1981 (Evans & Kaufman, 1981) and are pluripotent. They are sourced from the inner cell mass of the blastocyst, the stage of embryonic development 4-7 days after fertilization. In culture, they have been shown to have a high self-renewal capacity, dividing into more pluripotent cells nearly indefinitely (National Research Council and Institute of Medicine, 2002). Since they can produce any cell type in the body, they have been hailed as having great potential for future transplantation therapies, even including the growth of brand-new organs from scratch.
Adult stem cells (ASCs) are nonembryonic stem cells that normally replace worn-out cells and maintain tissues’ structural integrity. Though first discovered in the blood (Till & McCullough, 1961), they have also been found in specific niches in the stomach, muscle tissues, skin, brain, and heart (Gurusamy et al., 2018). Despite their limited differentiation potential compared to ESCs, ASCs have been shown to aid in regenerating depleted cells or tissues for conditions such as type 1 (Carlsson et al., 2014) and type 2 diabetes mellitus (Bhansali et al., 2017). The success of bone marrow transplants for leukemia therapy relies on hematopoietic stem cells (HSCs), a type of adult stem cell that can differentiate into all of the different cells found in the blood (Hussen et al., 2024). Unlike ESCs, ASCs can be sourced allogenically, which circumvents ethical concerns surrounding the extraction of ESCs from, and the consequent destruction of, human blastocysts.
Discovered in a research breakthrough in 2006 (Takahashi & Yamanaka, 2006), induced pluripotent stem cells (iPSCs) are adult cells that have been reprogrammed to exhibit pluripotency. Combining ESCs’ incredible adaptability with ASCs’ ethical feasibility, iPSCs have the potential to transform personalized medicine. Reprogramming a patient’s own adult cells “improves the integrity and efficiency of cell-based treatments and offers a potential path…to treat numerous illnesses and traumas” (Hussen et al., 2024). iPSCs also have applications in developing helpful in vitro disease models for research and in testing drugs on a cellular level.
Significant advancements have been made in the field of stem cell biology, and there are many emerging areas of promising research. For example, key signaling pathways and transcription factors that control stem cell differentiation pathways have been discovered (Hwang et al., 2008), and researchers have gained insight into the epigenetic modifications associated with reprogramming adult cells (Meissner, 2010). Currently, biomedical research is undergoing a revolution involving organoids, which are 3D stem cell-derived cultures that can act as in vitro models of human organs. Organoids have considerable potential in drug testing, disease modeling, tissue replacement or repair, and more (Zhu et al., 2025). In addition, recent Phase I/II clinical trials have shown that stem cell therapies replacing dopaminergic neurons in patients with Parkinson’s disease are safe and show promising potential for further development and testing (Sawamoto et al., 2025; Tabar et al., 2025). Clinical trials for several other conditions, including other neurodegenerative diseases such as ALS, ocular diseases, diabetes, and even dental illnesses, have also shown promise (Aly, 2020). Many more trials for a wide range of illnesses are under way around the world.
Currently, the only routine FDA-approved stem cell therapy is hematopoietic stem cell transplantation for treating leukemia or other blood-related diseases. Several hurdles still must be overcome in order for stem cell therapy to become a safer and more viable option for patients. These challenges include reducing the risk of rejection by the recipient’s immune system and tumorigenesis, in which transplanted stem cells may grow uncontrollably. Researchers must also develop methods to precisely control stem cell differentiation to minimize off-target effects. In addition, concerns remain regarding the ethical sourcing of ESCs, the premature marketing of unproven stem cell therapies, and the costs of large-scale stem cell production (Hussen et al., 2024).
Still, stem cells’ potential for treating numerous illnesses and revolutionizing biomedical research is undeniable. While many more studies are required to render stem cell therapies safe and effective, the rapidly developing field of regenerative medicine continues to move towards a future in which personalized cellular treatments become widely available.
Extraction and induced differentiation of pluripotent human embryonic stem cells.
Image from NIH (https://stemcells.nih.gov/info/basics/stc-basics), originally from “The promise of human embryonic stem cells in aging-associated diseases” by O. Yabut and H.S. Bernstein, 2011.
Rachel Lim is a staff writer at The Princeton Medical Review. She can be reached at rl5352@princeton.edu.
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