It all starts with a single cell.
Just one single cell will eventually become the trillions that make up the human body, consisting of hundreds of different types, each with its own unique task and function. From one cell comes blood, bone, skin, and hair. From one cell comes life.
But for a long time, the question was how? How could a single cell give rise to cells as vastly different as a neuron and a red blood cell, a bone cell and a muscle cell?
Early embryos are made up of just a few cells. How do they start deciding what to become? They need to choose different fates, and they need to become different parts of the developing human body."
Berna Sozen, PhD, Assistant Professor, Genetics, Yale School of Medicine (YSM)
The first major leap in our understanding of this process occurred in the 1960s when researchers discovered stem cells, specifically hematopoietic stem cells capable of replenishing the body's blood.
"The discovery of stem cells profoundly reshaped modern biology because it forced scientists to rethink what cells are capable of and how living systems are organized," says Haifan Lin, PhD, Eugene Higgins Professor of Cell Biology at YSM and founding director of the Yale Stem Cell Center. "It replaced a static view of biology with one centered on potential, regulation, and plasticity. This shift continues to shape research today."
Stem cells have transformed our understanding of tissue organization and development, how we age and how we heal. They have deepened our knowledge of diseases and our methods to study them. And they have opened new avenues for personalized medicine and therapies.
And yet so many questions remain. What governs when and how these cells divide, and what happens when those processes go awry? How can we harness those properties for researchers to model everything from complex neurological diseases to human embryological development?
At Yale School of Medicine, hundreds of researchers are working to answer these questions. Whether it's bone, blood, or hair, expanding the foundations of fundamental stem cell biology is the key to eventually treating a myriad of human diseases.
Stem Cell Therapies and Practical Challenges
When stem cells divide, say, to produce a red blood cell, the mother hematopoietic stem cell will produce one daughter blood cell, and one daughter hematopoietic stem cell. While a new daughter stem cell can continue to divide, the daughter blood cell, known as a partially differentiated progenitor cell, will only divide a limited number of times, eventually giving rise to a terminally differentiated red blood cell, which can no longer divide. Instead, the red blood cell will carry out its duties until eventual cell death. Such is the fate of a terminally differentiated cell.
At least that was the understanding until 2006, when Shinya Yamanaka, MD, PhD, discovered that, when exposed to embryonic transcription factors-proteins that can bind to specific sequences of DNA to turn genes on or off-adult cells, including adult tissue stem cells such as hematopoietic stem cells, could be reverted back to an embryonic stem cell state.
Embryonic stem cells exist in early embryos and can give rise to all cell types in the body, unlike specialized adult stem cells that are localized to specific tissues. Thus, Yamanaka's discovery, which earned him a Nobel Prize in Physiology or Medicine, gave researchers the ability to generate essentially any type of cell in the body-and ushered in a new era of stem cell biology and medicine.
"The Yamanaka discovery reshaped biology by proving that cell fate is reversible, expanding ethical and research possibilities, enabling patient-specific applications, and redefining biological identity as flexible rather than fixed," says Lin. "It fundamentally changed how scientists think about what cells are-and what they may become."
To this end, scientists and clinicians have been studying the use of these cells, called induced pluripotent stem cells, or iPSCs, to treat conditions such as macular degeneration and type 1 diabetes. But as groundbreaking as induced pluripotency is, turning mature, differentiated cells back into an induced pluripotent state is not without challenges.
For instance, exposing cells to transcription factors does not guarantee that they will always revert back to a stem state. In fact, induced pluripotency can take weeks, and may only succeed in less than 1% of cells.
"Not all starting cells are equally prone to revert back," says Shangqin Guo, PhD, associate professor in cell biology at YSM.
Guo studies the properties that dictate cell fate, and in 2014, she and her team discovered a special type of cell that was particularly good at being reprogrammed. These cells, called granulocyte monocyte progenitors (GMPs) were far more plastic than other cell types that might be used for reprogramming, such as skin fibroblasts.
"Normally, GMPs make bacteria-fighting white blood cells, but when we take them out and give them Yamanaka factors, they turn into iPSCs much more easily," Guo says. "We're still working to understand what gives these particular blood cell types this special power that makes them plastic, such as by comparing them to other blood cell types or fibroblasts."
GMPs reside deep in the bone marrow, making them harder to access than cells from blood draws or skin biopsies. Ultimately, says Guo, understanding what makes GMPs plastic could allow researchers to draw out those same properties from more accessible cells and harness the newfound plasticity to derive more cell types besides iPSCs.
"We are really working to understand how to turn cells that you can spare into whatever cell types that you may need to heal," Guo says. "Imagine a personal cell bank that one day, if you ever run into the need, we know how to make them for you. It'll be like you asking, 'Could I have a new heart or better kidney since mine are failing?'"
Stem Cell "Nightclubs"
Efficiently reverting mature cells in a petri dish to the stem state is just one piece of the puzzle. Keeping them-specifically, keeping hematopoietic stem cells-in that stem state is another challenge entirely.
In the body, hematopoietic stem cells live for a remarkably long time, remaining dormant for years and only occasionally waking up every so often to divide to make blood cell progeny. But their dormancy is strange, says Joao Pereira, PhD, associate professor of immunobiology at YSM, who likens the surrounding environment of the hematopoietic stem cell to that of a molecular nightclub; the stem cells are constantly bathed in signals that tell them to activate and divide, signals completely incompatible with their usual dormant state.
"A lot of these signals are the same types of signals that cause cells to go into division and differentiation," Pereira says. "What is it that keeps them asleep knowing that they are constantly receiving activating signals, almost as if they are sound asleep in a nightclub?"
In the petri dish, however, it's a different story. The cells can't seem to ignore the party and fail to remain dormant and undifferentiated for long. This poses a challenge for researchers hoping to modify the cells and use them for research or clinical trials. The researchers want the cells to pause, but they keep trying to differentiate into mature cells.
Pereira and his lab are working to figure out what, molecularly, keeps cells asleep even though they are in a very stimulating environment.
"We need to know all the ingredients that we can put in a petri dish to make sure that we can control the cell," he says. "Can we manipulate these mechanisms and actually have stem cells in a petri dish that are in a stem state and stay in a stem state while one goes in and makes the edits that we need to fix genetic diseases?"
Understanding Unique Stem Cell Niches
Interestingly, though, not all of these stem cell "nightclubs" are the same.
Hematopoietic stem cells reside within the bone marrow, but even across different bones, there's variation. Bong Ihn Koh, PhD, assistant professor of comparative medicine at YSM, studies the stem cell niche in the bones of the skull and face, highly unique environments compared to other bone marrow compartments.
In 2024, Koh discovered that not only does the bone marrow in the skull expand substantially throughout life, but it also doesn't seem to age.
"Bone marrow tends to decrease in function as we age, and this is why we have all these immune problems as we're aging," Koh says. "But the skull bone marrow tends to stay healthy and constantly increases blood production from the healthy microenvironment."
Koh and his lab are working to figure out precisely what makes the microenvironment in the skull bone marrow, and potentially other craniofacial bones, so resilient. In other words, what's the secret keeping the nightclub in the skull thriving while the body's other nightclubs shutter?
The secret may lie in the blood vessels feeding these microenvironments. "We are currently identifying cellular and molecular targets in the skull bone marrow that might be able to confer that resilience to other stem cell microenvironments and prevent stem cell niche aging and functional deterioration," Koh says.
It's not just the blood vessels that are critical for the stem cell microenvironment, though. Valentina Greco, PhD, Carolyn Walch Slayman Professor of Genetics at YSM, would argue that all of the different cell types play a critical role in the functioning and regeneration of stem cell environments in locations like hair and skin.
"We currently lack the capacity to understand how the same cells within that tissue behave over time because we tend to do this analysis in a static manner," Greco says. "Because the skin is made of different cell types, understanding how multiple different cell types coexist, communicate, and interact can tell you what is happening within each cell type."
To this end, Greco's team studies how stem cells interact in live organisms, rather than taking snapshots of cells across different mice to infer their behaviors. Using bioengineered mouse models, she and her team can track fluorescence signals from stem cells in the skin over extended periods of time.
"By keeping a mouse intact and looking at cells that are alive within a native context in an organism that keeps living day after day, you're really putting together pieces of the puzzle that were missing," she says.
Using this approach, Greco and her team have been able to observe over time how stem cells act as sentinels that detect and shrink tumors, compensate for the loss of cells in neighboring areas due to injury or aging, and rely on neighboring cells to decide when to divide or differentiate.
"There are so many questions in understanding how a system works over time with the framework of the collective," Greco says. "We are influenced by structure, architecture, incentive, all true whether you're speaking about a population of humans versus a population of cells."
Developing Stem Cell Models of Human Development and Disease
By deepening our understanding of how stem cells divide, how they organize and interact with each other, and how they can be used efficiently in the lab, researchers can then use them to model complex conditions and human states.
Sozen, for example, studies mammalian embryonic development. She's particularly interested in the gastrulation stage when organ progenitors begin to form, and how cells decide what routes to take at this stage. But to study human embryo development, researchers need human embryos, which can be technically and ethically challenging, Sozen says. Thus, Sozen and other labs have figured out how to use stem cells to generate models of human embryos.
"We have generated a platform where you can aggregate the cells and they reorganize within a few days to grow models of embryonic development," Sozen says. "You have this snapshot to look into human development without using human embryos."
Studying development at the gastrulation stage could be particularly useful for understanding early pregnancy failures or even fetal developmental disorders. "Using stem cell models becomes very important because if you can understand what's going awry, then you can develop therapeutic approaches or solutions," Sozen says.
Researchers have also been able to use stem cells to model organs, from intestines to livers to lungs. Kristen Brennand, PhD, Elizabeth Mears and House Jameson Professor of Psychiatry at YSM, uses stem cells to model the brain and certain psychiatric conditions that can affect it. Stem cell models, she says, offer a way to understand disease processes while they are happening, rather than after the fact.
"A stem cell model allows you to recapitulate all of the disease processes in a human context in a dish and watch real time what's happening," Brennand says. "We can make stem cells and then make any cell type in the body from anyone on the planet, and then we can also add in genetic risk or remove genetic risk."
Brennand is particularly interested in understanding how genetic variants interact with the environment to predict disease outcomes over a person's lifetime. She has studied conditions such as schizophrenia, post-traumatic stress disorder, and autism, all by using stem cell models of the brain made from the patient's own cells. This is a valuable approach, Brennand says, because it means that the models contain all of the same genetic variants that the person already has in their actual brain.
Psychiatric conditions are extremely complex, with hundreds or thousands of variants that couldn't be simply addressed by editing a single mutation. But Brennand envisions a future where all of these variants can be translated into risk factors that then point to potential preventative measures.
"The idea is that we would take the diseases that you're at greatest risk for and treat them," Brennand says. "I would much rather prevent your future disease than treat it after you have it."
A Center for Stem Cells
Since 2006, stem cell researchers at Yale have been able to join forces under a unified platform: the Yale Stem Cell Center.
At the time of its founding, stem cell research was growing quickly but was very fragmented. Lin, the founding director of the center, envisioned a unit that would serve as an epicenter to combine the strengths of different faculty and have an impact across the entire university.
"I knew that there were so many faculty members on Yale's campus that wanted to work on stem cells, but they didn't have the techniques or know-how," Lin says. "I thought I could convert these faculty members who were already leaders in their corresponding fields into stem cell researchers."
After its first year, the center was the intellectual home to 26 labs. Today, that number has exceeded 100 and continues to grow, with Lin actively working to increase the center's translational and clinical work.
But even as the center expands, Lin maintains the importance of conducting fundamental scientific research. Lin himself studies some of the mechanisms of small RNAs and gene expression.
"At Yale Stem Cell Center, we are making uniquely important contributions," says Lin. "Those contributions are both at the fundamental knowledge level, but also at the translational and clinical level."
Like the multifaceted environments of stem cells themselves, combining fundamental biology and clinical stem cell work cannot happen in isolation, a sentiment echoed by the center's faculty members.
"The way we look at cells can inform the way we look at the world," says Greco. "That's why we need so many different people. We may be insignificant as a single point, but together, there is so much strength."
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