Pluripotent stem cells come from two main sources: the inner cell mass of early human embryos and, since 2006, from ordinary adult cells that have been reprogrammed back to an embryonic-like state in the laboratory. These two routes produce embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), respectively. Both can generate virtually any cell type in the human body, which is what makes them so valuable for medicine and research.
The Natural Source: Early Embryos
In nature, pluripotent cells exist briefly during the first days of embryonic development. After a sperm fertilizes an egg, the resulting single cell (the zygote) is totipotent, meaning it can produce every cell type needed to build a full organism, including the placenta. The zygote is the only cell considered indisputably totipotent.
As that single cell divides, it forms a hollow ball called a blastocyst by about day five. Inside the blastocyst sits a small cluster of cells called the inner cell mass. These cells are pluripotent: they can become any tissue in the body (skin, nerve, muscle, blood, bone, organs) but can no longer form the placenta and other support tissues. This is the first major fork in embryonic development, where cells lose totipotency and become pluripotent instead.
The inner cell mass then undergoes a second split. Some of its cells become the primitive endoderm (which helps form the yolk sac), while others become the epiblast, which eventually gives rise to the entire fetus. Both of these stages contain pluripotent cells, but they behave differently. Cells from the earlier, pre-implantation stage are called “naïve” pluripotent cells, and cells from the later, post-implantation epiblast are called “primed.” Naïve cells grow in round, dome-shaped colonies and have broadly low levels of DNA modification, keeping many genes in an open, accessible state. Primed cells grow flat, in a single layer, and have more extensive DNA modifications that begin to narrow their options. Both types share core genetic circuitry, but they use it differently, activating different sets of target genes.
How Embryonic Stem Cells Are Derived
James Thomson and colleagues first isolated human embryonic stem cells in 1998, deriving them from blastocysts donated from fertility clinics. Those original cell lines proliferated in the lab for four to five months while still retaining the ability to form tissues from all three embryonic layers: gut lining (endoderm), bone and muscle (mesoderm), and nerve and skin tissue (ectoderm).
In the United States, NIH guidelines require that embryos used for stem cell derivation come from surplus embryos created for reproductive purposes that donors no longer need. No payment of any kind is permitted for donated embryos. Donors must be told that the research won’t benefit them medically, that commercial products could result, and that they won’t share in any profits. Donors can withdraw consent at any point before the cells are actually derived.
Once removed from the embryo, inner cell mass cells are placed in carefully controlled lab conditions to keep them pluripotent. Early methods relied on a bed of mouse feeder cells to provide the right chemical signals. Modern protocols have moved toward fully defined, animal-free conditions. Cells are grown on synthetic surfaces coated with specific proteins like laminin or vitronectin, and fed chemically defined media containing growth factors that maintain their undifferentiated state. Surface properties matter: smooth, rigid surfaces support self-renewal, while soft surfaces push cells toward differentiation.
Induced Pluripotent Stem Cells: Rewinding Adult Cells
The second major source of pluripotent stem cells sidesteps embryos entirely. In 2006, Shinya Yamanaka’s lab showed that introducing just four genes into ordinary adult cells could reprogram them into a pluripotent state. These four genes, now called the Yamanaka factors, produce proteins (Oct4, Sox2, Klf4, and c-Myc) that essentially rewind a cell’s developmental clock, erasing its specialized identity and restoring embryonic-like flexibility. The resulting cells are called induced pluripotent stem cells, or iPSCs.
Almost any dividing cell in the body can serve as starting material. Skin fibroblasts, typically collected through a small biopsy, remain the most common source. But researchers have successfully reprogrammed blood cells (from a standard blood draw or umbilical cord blood), kidney cells shed in urine, hair follicle cells from plucked hairs, cheek cells collected with a simple swab, liver cells, pancreatic cells, joint tissue cells, and even cells from extracted wisdom teeth. The less invasive the collection, the more practical the approach for patients. Blood and urine samples are especially attractive because they require no surgical procedure at all.
The choice of starting cell can affect reprogramming speed and efficiency, but all routes converge on the same result: cells that closely mirror embryonic stem cells in their ability to become any tissue type.
Pluripotent vs. Totipotent vs. Multipotent
These terms describe a hierarchy of flexibility. Totipotent cells, only the zygote and possibly its first few divisions, can produce everything: the embryo, the placenta, and all supporting tissues. Pluripotent cells can generate all the cell types found in an adult body (over 200 types, spanning all three embryonic germ layers) but cannot form the placenta. Multipotent cells are more restricted, typically producing several cell types within a single tissue family. A blood stem cell, for example, can make red cells, white cells, and platelets, but not nerve cells or muscle.
Why Pluripotent Cells Need Careful Handling
The same unlimited potential that makes pluripotent stem cells medically exciting also makes them dangerous if used carelessly. When undifferentiated pluripotent cells are transplanted into the body, they can form teratomas: tumors containing a chaotic mix of tissues from all three germ layers (you might find teeth, hair, and gut tissue jumbled together in one mass). The risk comes specifically from any pluripotent cells that persist in a batch of cells that were supposed to be fully differentiated before transplantation.
Researchers use several strategies to eliminate these stowaways. One approach sorts cells using surface markers unique to pluripotent cells, physically removing them from the population. A second strategy engineers a “suicide gene” into the stem cells, controlled by a genetic switch that’s only active in undifferentiated cells. When triggered, it kills any remaining pluripotent cells while leaving the differentiated, therapeutic cells unharmed. A third approach uses chemicals that exploit a survival vulnerability specific to pluripotent cells: these cells depend entirely on a protein called survivin to stay alive, so drugs that block survivin kill pluripotent cells selectively without affecting mature cells.
Where Things Stand Clinically
As of December 2024, 116 clinical trials using pluripotent stem cell-derived therapies have received regulatory approval worldwide, testing 83 different cell products. The most common targets are eye diseases, neurological conditions, and cancer. More than 1,200 patients have received these therapies so far, with over 100 billion cells administered collectively. No widespread safety concerns have emerged from this growing body of clinical experience, though trials continue to track long-term outcomes.
The practical significance of having two sources of pluripotent cells is substantial. Embryonic stem cells remain the gold standard for consistency and are well-characterized after more than 25 years of research. iPSCs offer the advantage of being genetically matched to individual patients, reducing the risk of immune rejection, and they avoid the ethical debates surrounding embryo use. Both types are actively moving from the lab bench into patient care.