Stem Cells in Animals: Types, Roles, Healing

Stem cells are the unspecialised cells from which every animal body is built, maintained and repaired. A stem cell is a cell that has not yet decided what it will become: it can copy itself to make more stem cells, and it can also give rise to specialised cells such as muscle fibres, nerve cells, skin cells or blood cells. Every animal, from a sponge to a human, begins life as a single cell that divides into stem cells, and the whole body is the result of those cells choosing different fates. Even in an adult, stem cells keep working quietly in the bone marrow, the gut, the skin and the muscle, replacing cells that wear out and repairing damage after injury.

The reason stem cells attract so much attention is that they sit at the junction of development, healing and medicine. They explain how an embryo builds itself from one cell, how a planarian worm can regrow its whole body from a fragment, and why a bone marrow transplant can cure a blood disease. They also explain some of the hardest problems in biology: why mammals cannot regrow a lost limb, why stem cells can sometimes form tumours, and why the most powerful stem cells raise ethical questions. This article explains what stem cells are, the ladder of potency from totipotent to unipotent, the three great sources of stem cells, the tissues they maintain, the animals that use them to regenerate, and their veterinary, conservation and medical promise, in plain language and at full depth.

Stem cells are not one kind of cell. They are a family of cells that differ in what they can become and where they live. The most powerful are found only in the earliest embryo, and their power narrows as development proceeds: the cells of the early embryo can make anything, the stem cells of the adult can make only the cells of their own tissue, and some can make only one cell type. Understanding stem cells therefore means understanding potency, the measure of what a cell can still become, and the niche, the small neighbourhood in the body that keeps a stem cell a stem cell. The sections below follow that logic, from the definition, through the potency ladder, through the tissues, and out to the animals, the clinic and the conservation ark.

Stem Cells at a Glance

A stem cell is defined by two abilities that no specialised cell has. The first is self-renewal: when a stem cell divides, at least one of its daughters remains a stem cell, so the stem cell population does not run out. The second is differentiation: a stem cell can produce daughter cells that specialise into particular cell types, such as a red blood cell, a skin cell or a neurone. Most ordinary cells can do neither: a skin cell divides to make more skin cells, and a muscle fibre does not divide at all. A stem cell does both, and the balance between the two is what keeps a tissue supplied for a lifetime.

Stem cells divide in two ways. In a symmetric division, a stem cell produces two stem cells, which expands the stem cell pool, and this is common during growth and after injury. In an asymmetric division, a stem cell produces one stem cell and one daughter that will differentiate, which keeps the pool constant while supplying new specialised cells. The choice between the two is controlled by signals from the niche and by the orientation of the division itself. When the balance fails, the consequences are serious: too little self-renewal and a tissue runs out of cells, too much and the cells may grow out of control.

The word "stem" in stem cell is a metaphor from plant biology: the stem of a plant is the part from which branches grow, and a stem cell is the part of a tissue from which specialised cells branch off. The term was first used for blood-forming cells in the early twentieth century, when the Russian histologist Alexander Maximow proposed in 1908 that all blood cells descend from a single common ancestor cell, a claim that took decades to prove. The idea was confirmed in the 1960s, when James Till and Ernest McCulloch showed that a single mouse bone marrow cell could repopulate the whole blood system. Today we know that stem cells exist in almost every animal tissue, and that the same two properties, self-renewal and differentiation, define them all.

What Is a Stem Cell?

To call a cell a stem cell, biologists require evidence of both self-renewal and differentiation, and the gold standard is a functional test: a single cell must be able to rebuild the tissue it belongs to. For blood stem cells, that test is the bone marrow transplant, in which a single haematopoietic stem cell can repopulate the blood of an irradiated mouse. For skin stem cells, it is the growth of a complete sheet of epidermis from a small biopsy, which is how burns are treated. For intestinal stem cells, it is the growth of a miniature gut, an organoid, from a single stem cell in a dish. A cell that cannot do this is a progenitor, a cell that can divide a few times and make a limited range of cell types, but that cannot renew itself indefinitely.

The distinction between a stem cell and a progenitor matters, because the two behave differently. A stem cell divides rarely and slowly, which protects its DNA from copying errors, and it lives a long time. A progenitor divides rapidly and briefly, producing the bulk of a tissue's cells, and then it is exhausted. In the gut, for example, the stem cells sit at the bottom of the crypts and divide about once a day, while their progeny, the transit-amplifying cells, divide several times a day as they move up the villus, differentiate, and are shed within a few days. The stem cell is the permanent resident; the progenitors are the short-lived workforce.

Stem cells are also defined by what they are not. They are not specialised: a stem cell has no haemoglobin, no myosin, no melanin and no synapses, and it cannot carry oxygen, contract, make pigment or transmit a nerve impulse. It is a blank cell, with an open genome, ready to switch on the genes of whichever cell type it is told to become. That openness is both its power and its danger. The same open genome that lets a stem cell become anything also lets it grow without control if the signals that guide it are lost, which is why pluripotent stem cells can form tumours. A stem cell is therefore a cell defined by potential, and the biology of stem cells is the biology of how potential is kept, used and, when necessary, restrained.

The Potency Ladder: From Totipotent to Unipotent

Potency is the measure of what a stem cell can become, and it forms a ladder with five rungs. At the top is the totipotent cell, which can make a complete organism, including the extra-embryonic tissues such as the placenta. Only the fertilised egg, the zygote, and the cells of the very early embryo, up to the eight-cell stage in mammals, are totipotent. Each of these cells, placed in the right environment, could in principle develop into a whole animal, which is how identical twins arise: a two-cell embryo splits, and each cell, still totipotent, makes a complete individual.

One rung down is the pluripotent cell, which can make every cell type of the body, all three germ layers, but not the extra-embryonic tissues. The embryonic stem cells of the inner cell mass are pluripotent, and so are the induced pluripotent stem cells made in the laboratory. A pluripotent cell can become a neurone, a muscle fibre, a blood cell or a gut cell, but it cannot make a placenta on its own, and it cannot make a whole animal without help. Below pluripotency is multipotency: a multipotent stem cell can make several cell types, but only within one lineage. The haematopoietic stem cell of the bone marrow is multipotent, because it makes all the blood cells, red cells, white cells and platelets, but it cannot make a skin cell or a neurone. Oligopotent cells can make only a few closely related types, and unipotent cells can make only one type, such as a muscle satellite cell, which makes only muscle fibres, or a spermatogonial stem cell, which makes only sperm.

The ladder runs in one direction during development: potency narrows as cells specialise. The zygote is totipotent, the inner cell mass is pluripotent, the germ-layer progenitors are multipotent, and the tissue stem cells of the adult are multipotent or unipotent. The great surprise of the last twenty years is that the ladder can be climbed back up: an adult skin cell can be reprogrammed into a pluripotent stem cell, which is the induced pluripotent stem cell. Potency is therefore not a one-way street, and the reprogramming of adult cells has changed both medicine and the ethics of the field. The table below sets out the five rungs of the ladder.

Potency	What the cell can become	Example	Where it is found
Totipotent	A complete organism, including placenta	Zygote, early blastomeres	Fertilised egg, up to the 8-cell embryo
Pluripotent	All body cell types, all three germ layers	Embryonic stem cell, iPSC	Inner cell mass of the blastocyst; laboratory
Multipotent	Several types within one lineage	Haematopoietic stem cell	Bone marrow
Oligopotent	A few closely related types	Lymphoid progenitor	Bone marrow, thymus
Unipotent	A single cell type	Muscle satellite cell	Under the basal lamina of muscle fibres

Embryonic Stem Cells

Embryonic stem cells are the pluripotent cells of the inner cell mass, the cluster of cells inside the blastocyst that will become the body of the animal. In mammals, the blastocyst forms about five to seven days after fertilisation, and it is a hollow ball of cells: an outer layer, the trophoblast, which will make the placenta, and the inner cell mass, which will make the embryo. If the inner cell mass is removed and grown in a dish, its cells keep dividing without differentiating, and they remain pluripotent, able to become any cell type of the body. That is the embryonic stem cell, and it is the most powerful stem cell that can be kept in culture.

The first embryonic stem cells were isolated from mice in 1981, by Martin Evans and Matthew Kaufman in Cambridge and independently by Gail Martin in San Francisco, and the first human embryonic stem cells were isolated in 1998 by James Thomson at the University of Wisconsin. The mouse work showed that embryonic stem cells could be grown, frozen, genetically altered and put back into an embryo, where they contributed to every tissue, including the germ line, which is how genetically modified mice are made. The human work showed the same cells could be grown from surplus embryos donated after IVF treatment, and it opened the possibility of making any human cell type in the laboratory.

Embryonic stem cells divide indefinitely in the dish, which is both their promise and their problem. Their indefinite division means a single line can supply cells forever, and their pluripotency means those cells can be directed into neurones, heart muscle, insulin-producing beta cells or retinal cells. But the same properties make them dangerous: if undifferentiated embryonic stem cells are placed in an adult body, they can form a teratoma, a tumour containing tissues from all three germ layers, such as bone, hair and gut lining, jumbled together. Embryonic stem cells are therefore never transplanted as they are; they are first differentiated in the dish into the desired cell type, and the differentiated cells are transplanted instead.

Adult Stem Cells and the Niche

Adult stem cells, also called somatic or tissue stem cells, are the stem cells that remain in the body after development is complete. They are multipotent or unipotent, and they live in small, protected neighbourhoods called niches. A niche is a microenvironment, a pocket of supporting cells, extracellular matrix and signals, that keeps the stem cell quiet, undifferentiated and alive. In the bone marrow, the niche is made of stromal cells, blood vessels and bone-lining cells. In the gut, it is the base of the crypt. In the skin, it is the bulge of the hair follicle. In the muscle, it is the space under the basal lamina. The niche tells the stem cell when to divide and when to stay still, and if the niche is destroyed, the stem cells are lost with it.

Adult stem cells divide rarely, which is a form of protection. Every division risks a copying error in the DNA, and a stem cell that divides rarely accumulates fewer errors than one that divides constantly. Many adult stem cells divide only a few times a year, and some divide only after injury. When they do divide, they often divide asymmetrically, producing one stem cell that stays in the niche and one daughter that leaves to differentiate. The daughter then divides rapidly as a transit-amplifying cell, producing the bulk of the tissue, and the stem cell itself returns to rest. This arrangement lets a tissue renew itself for a lifetime while keeping its stem cells safe.

The niche also explains why adult stem cells cannot simply be moved from one tissue to another. A blood stem cell taken out of the bone marrow and placed in the skin does not become a skin stem cell, because the signals it needs come from the bone marrow niche, not from the cell itself. The stem cell and its niche are a unit, and the behaviour of the cell is set as much by its surroundings as by its genes. This is also why ageing affects stem cells: as the niche ages, its signals weaken, the stem cells divide less well, and the tissue renews itself more slowly. The decline of the niche is one reason wounds heal more slowly and blood counts fall in old animals.

Induced Pluripotent Stem Cells (iPSCs)

Induced pluripotent stem cells, or iPSCs, are adult cells that have been reprogrammed back to pluripotency in the laboratory. The method was discovered in 2006 by Shinya Yamanaka at Kyoto University, who showed that introducing four genes, Oct4, Sox2, Klf4 and c-Myc, into a mouse skin fibroblast turned it into a cell indistinguishable from an embryonic stem cell. The four genes are transcription factors, proteins that switch other genes on and off, and together they reset the cell's identity, erasing the marks of its adult life and restoring the open genome of an embryonic cell. Yamanaka's human iPSCs followed in 2007, and in 2012 he shared the Nobel Prize in Physiology or Medicine with John Gurdon, whose earlier work on nuclear transfer had shown that an adult nucleus still contains all the information needed to make a whole animal.

iPSCs changed the field in two ways. First, they removed the need for embryos: a pluripotent stem cell could now be made from a skin sample, a blood sample or a urine sample, from any individual, at any age. Second, they made patient-specific stem cells possible: cells made from a person with a disease carry that person's own genes, including the mutation that causes the disease, so they can be used to study the disease in a dish and to test drugs on the patient's own cells. A skin sample from a person with Parkinson's disease, for example, can be turned into iPSCs and then into dopamine neurones, and the neurones can be studied to see exactly how they fail. That is disease modelling, and it is now routine.

iPSCs are not perfect. The reprogramming process is inefficient, only a small fraction of cells complete it, and the resulting cells carry an epigenetic memory of their tissue of origin, which can bias what they become. The original four factors include c-Myc, a gene that can promote cancer, and although safer cocktails have been developed, the risk of tumour formation means iPSCs are not transplanted as undifferentiated cells, any more than embryonic stem cells are. They are differentiated first, and the differentiated cells are transplanted. Even so, iPSCs have removed the central ethical objection to pluripotent stem cells, because no embryo is used, and they have made personalised stem cell medicine a practical goal rather than a hope.

Stem Cells in the Blood

The blood is the tissue where stem cells were first understood, and it is still the tissue where they are most used in medicine. The haematopoietic stem cell lives in the bone marrow, and it makes every blood cell: the red cells that carry oxygen, the white cells that fight infection, and the platelets that clot the blood. A human makes hundreds of billions of blood cells every day, and all of them descend from a small number of haematopoietic stem cells, a few tens of thousands in the whole marrow. Each stem cell divides rarely, and its progeny divide rapidly, passing through a series of progenitors, the myeloid and lymphoid lines, before becoming mature blood cells.

The haematopoietic stem cell is the only stem cell that is already a routine treatment. A bone marrow transplant, more precisely a haematopoietic stem cell transplant, replaces a patient's blood system with a donor's. It is used to treat leukaemia and lymphoma, where the patient's own blood cells are diseased, and immune deficiencies and some inherited blood disorders, where the blood system is broken. The patient's marrow is first cleared with chemotherapy or radiation, and then the donor's stem cells are infused, find their way to the marrow niches, and rebuild the blood. The first successful transplants were done in the late 1950s and 1960s, and E. Donnall Thomas received the Nobel Prize in 1990 for developing the treatment.

The blood also shows how tightly a stem cell is controlled. The haematopoietic stem cell must produce the right numbers of each cell type: too few red cells and the animal is anaemic, too few white cells and it cannot fight infection, too many and the blood becomes diseased. The control is exercised by signals from the marrow niche and by the body's demands: infection increases white cell production, bleeding increases red cell production, and the stem cell responds by changing how often it divides and which lineage its daughters enter. When the control fails, the result is leukaemia, a cancer of the blood in which a stem or progenitor cell begins to divide without restraint. Leukaemia is, in a real sense, a disease of stem cell regulation.

Stem Cells in the Skin

The skin is the largest organ of the body, and it is also one of the fastest-renewing. The epidermis, the outer layer of the skin, replaces itself completely every few weeks in a mammal, and the cells that make that possible are the epidermal stem cells of the basal layer. These cells sit on the basement membrane, attached to it by structures called hemidesmosomes, and they divide to produce daughters that move upward, differentiate into keratinocytes, fill themselves with keratin, die, and are shed from the surface. The whole journey from the basal layer to the surface takes about two to four weeks in human skin, and it never stops.

A second population of skin stem cells lives in the bulge of the hair follicle, a swelling on the side of the follicle that acts as a niche. The bulge stem cells make the hair itself, cycling through growth, rest and shedding, and they also serve as a reserve for the epidermis: after a wound, bulge stem cells leave the follicle, migrate into the wound and help rebuild the epidermis. The skin therefore has two stem cell pools, one for daily renewal and one for repair, and the two work together when the skin is injured. A cut heals because the basal stem cells at the wound edge divide faster and the bulge cells move in to help, and the new epidermis they make is, at first, thin and fragile, thickening only as the stem cells re-establish their niches.

Skin stem cells are also a medical success story. A small biopsy of a patient's skin can be grown in the laboratory into sheets of epidermis large enough to cover a burn, and the sheets are grafted onto the wound, where they take and grow. The method, developed in the 1970s and 1980s, has saved the lives of patients with burns over most of their body. The same principle is now being extended: skin stem cells can be turned into iPSCs, and the iPSCs into other cell types, which makes the skin a convenient starting point for personalised stem cell medicine. The skin is, in this sense, both a tissue maintained by stem cells and a source of stem cells for the rest of the body.

Stem Cells in the Gut

The gut lining is the fastest-renewing tissue in a mammal's body. The epithelium of the small intestine replaces itself every three to five days, a rate that no other tissue matches, and the renewal is driven by stem cells at the base of the crypts of Lieberkühn, the small pits between the villi. Each crypt contains a handful of stem cells, marked by the protein Lgr5, which divide every day to produce daughters that move up the villus, differentiate into absorptive cells, mucus-secreting goblet cells, hormone-secreting enteroendocrine cells or antimicrobial Paneth cells, and are shed from the villus tip within days. The whole lining is a conveyor belt, and the stem cells at the bottom are its motor.

The intestinal stem cell was identified in 2007, when Hans Clevers and his colleagues showed that Lgr5 marks the stem cells of the mouse crypt, and that a single Lgr5 cell can rebuild a whole crypt and villus. The discovery was confirmed when a single intestinal stem cell, grown in a dish with the right factors, built a miniature gut, an organoid, complete with crypts, villi and all four cell types. The organoid is now a standard laboratory tool: gut organoids are used to study intestinal disease, to test drugs, and to grow tissue for transplantation. The same principle has been extended to the stomach, the liver and the pancreas, and organoids are now grown from many tissues.

The gut's speed of renewal is also its weakness. The gut lining is exposed to food, microbes and toxins, and it is damaged by chemotherapy and radiation, which kill dividing cells. The stem cells are the reason the gut recovers: as long as the stem cells survive, the lining rebuilds itself in days. But if the stem cells are destroyed, the gut cannot renew, and the animal dies. The gut therefore shows both the power and the vulnerability of a stem-cell system: a tissue that renews in days depends entirely on a handful of cells at the bottom of each crypt, and protecting those cells is the same as protecting the tissue.

Stem Cells in Muscle and Nerve

Muscle is repaired by satellite cells, the stem cells that lie under the basal lamina of each muscle fibre. A satellite cell is unipotent: it can make only muscle. In a resting muscle, the satellite cells are quiet, tucked between the fibre and its surrounding membrane, and they divide only when the muscle is injured or exercised hard. After an injury, they activate, divide rapidly, and their daughters fuse with each other or with damaged fibres to form new muscle, while some daughters return to the satellite position to keep the pool supplied. A muscle that is exercised grows because its satellite cells add new nuclei to the fibres, and a muscle that is injured heals because its satellite cells rebuild the fibres.

The satellite cell pool is finite, and it declines with age. In an old animal, there are fewer satellite cells, and those that remain respond more slowly to injury, which is one reason old muscles heal poorly and lose mass. The decline is driven partly by the cells themselves and partly by their niche: the signals that keep satellite cells ready weaken with age, and the muscle's environment becomes more inflammatory. Exercise helps, because contraction releases factors that activate satellite cells, and this is one reason that regular movement protects muscle in old age. The muscle stem cell is therefore a clear example of a stem cell whose performance is set by age, use and environment together.

The nervous system is the opposite of the gut: it renews slowly, and in most mammals it barely renews at all. The brain contains neural stem cells in two niches, the subventricular zone beside the lateral ventricles and the dentate gyrus of the hippocampus, and these cells make new neurones throughout life, but only in small numbers and only in those two places. Most of the brain has no stem cells at all, which is why a brain injury does not heal the way a skin wound does. Birds and fish are different: a songbird makes new neurones in its song centres every season, and a zebrafish can regrow large parts of its brain. The mammalian brain's limited stem cells are one reason that nerve damage is so hard to treat, and one reason that stem cell therapy for the nervous system is among the most difficult goals in the field.

Stem Cells in Development

Development is the story of stem cells choosing fates. A fertilised egg divides into totipotent blastomeres, and by the blastocyst stage the inner cell mass is pluripotent. The cells of the inner cell mass then form the three germ layers: the ectoderm, which will make the skin and the nervous system; the mesoderm, which will make the muscle, blood, bone and kidney; and the endoderm, which will make the gut and the lungs. Each germ layer then produces its own progenitors, and each progenitor produces the stem cells of a particular tissue. The whole body is built by a branching tree of choices, and at every branch a cell gives up some potency to gain a fate. The process is explained step by step in our article on embryonic development in animals, from fertilisation through cleavage, blastula and gastrulation to organ formation.

The choices are made by signals. A cell becomes ectoderm or mesoderm because of the signals it receives from its neighbours, and the signals are themselves produced by cells that have already chosen. The process is a cascade: a few signals at the start set off a chain of decisions that ends in hundreds of cell types. The signals include well-studied families, the Wnt, BMP, Hedgehog and Notch pathways, and each is used again and again in different places, so that the same signal can mean different things depending on the context. The precision of development comes from the combination: a cell reads several signals at once, and the combination tells it exactly what to become.

Development also shows why stem cells are so carefully controlled. If a cell chooses the wrong fate, or fails to choose at all, the embryo is malformed. The control is exercised by the niche, by the signals, and by the cell's own internal state, and the three must agree. When they do not, the result is a birth defect, or a tumour. The study of development is therefore also the study of stem cell regulation, and the two fields, developmental biology and stem cell biology, are now the same field seen from two sides.

The germ line has its own stem cells. In males, spermatogonial stem cells divide throughout life to produce sperm, and in females of many animals, oogonial stem cells do the same for eggs, although mammals are generally thought to be born with their full supply of eggs. The contrast between animals that reproduce asexually and those that reproduce sexually is also a contrast in how stem cells are used, and our comparison of asexual and sexual reproduction in animals explains the trade-offs in full.

Growth and Everyday Repair

After development is complete, stem cells change jobs: from building the body to maintaining it. The maintenance is not trivial. A mammal's blood, gut and skin are replaced constantly, and the replacement is driven entirely by stem cells. The blood is remade every day, the gut lining every few days, and the skin every few weeks, and the animal never notices, because the stem cells supply new cells at exactly the rate the old ones are lost. The maintenance is so reliable that we forget it is happening, and we notice it only when it fails, as in anaemia, when the blood stem cells cannot keep up, or in a gut that cannot renew after chemotherapy.

Repair after injury is the same machinery working faster. When the skin is cut, the basal stem cells at the wound edge divide more rapidly, and the bulge stem cells of the hair follicles migrate in to help. When a muscle is torn, the satellite cells activate and rebuild the fibres. When the liver is damaged, its cells divide, and recent work shows the liver also contains stem-like cells that can rebuild it. The repair is not perfect: skin heals with a scar, because the new tissue is laid down quickly and without the original organisation, and muscle heals with fibrosis if the injury is large. The scar is the price of speed, and it is the reason that repair is not the same as regeneration, which rebuilds the original structure without a scar.

The difference between repair and regeneration is a matter of degree, and it is set by the animal. A mammal repairs its skin with a scar and cannot regrow a limb. An axolotl regenerates its limb without a scar. A planarian regenerates its whole body. The difference is not that mammals lack stem cells: they have them. The difference is in what the stem cells are allowed to do, and the signals that guide them. Understanding that difference is the central question of regenerative biology, and it is the reason that animals which regenerate are studied so intensively.

Regeneration: Animals That Rebuild

Regeneration is the most dramatic use of stem cells in the animal kingdom, and it is best seen in a small flatworm, the planarian. A planarian cut into pieces regrows a complete worm from each piece, head, tail, gut and brain, and it does so with stem cells called neoblasts. Neoblasts are pluripotent adult stem cells, and they make up about a fifth to a third of all the cells in the worm's body. When the worm is cut, the neoblasts gather at the wound, divide, and rebuild whatever is missing, and they do it by reading the body's positional information, the signals that tell a cell whether it is at the head end or the tail end. A fragment the size of a grain of sand can rebuild a whole planarian, because its neoblasts can make every cell type the worm has.

The axolotl, a Mexican salamander, is the vertebrate champion of regeneration. It regrows whole limbs, and it does so by forming a blastema, a mound of undifferentiated cells at the stump, which then grows and differentiates into bone, muscle, skin, nerve and blood vessels in the right pattern. The blastema is not made of pluripotent stem cells: it is made of cells that were once specialised, muscle cells, skin cells and connective tissue cells, which have dedifferentiated, gone back to a stem-like state, and then redifferentiated into the missing parts. The axolotl also regenerates its spinal cord, parts of its heart and parts of its brain, and it does all of it without scarring. Our article on regeneration in animals explains the blastema, the neoblast and the reasons mammals scar, in full.

Other animals regenerate in their own ways. A starfish regrows an arm, and in some species a single arm can regrow a whole animal. A zebrafish regrows its fins and can repair a damaged heart, replacing the scar with new muscle. A deer regrows its antlers every year, the fastest-growing bone known, driven by stem cells in the pedicle. A lizard regrows its tail, although the new tail is a simpler structure, with a cartilage rod instead of vertebrae. A hydra, a tiny freshwater animal, renews its whole body continuously from interstitial stem cells, and it does not seem to age at all. The table below compares the champions.

Animal	What it regrows	Stem cells involved	Scar?
Planarian	Whole body from a fragment	Neoblasts, pluripotent	No
Axolotl	Limb, spinal cord, heart, brain	Blastema from dedifferentiated cells	No
Zebrafish	Fins, heart muscle	Resident progenitor cells	No, heart muscle replaced
Starfish	Arms, sometimes whole body	Coelomic and epidermal progenitors	No
Deer	Antlers every year	Pedicle stem cells	No
Lizard	Tail	Blastema-like cells	Simpler tail, cartilage rod
Human	Skin, gut, blood, liver	Tissue stem cells	Yes, skin and muscle scar

Stem Cells in Animals Beyond Humans

Most stem cell research is done on humans and mice, but the most interesting stem cells are found elsewhere. The sponge, the simplest animal, has archaeocytes, wandering cells that can become any cell type in the sponge's body, including the collar cells that feed it and the spicules that support it. A sponge can be pushed through a sieve, and its cells will reaggregate and rebuild the sponge, because the archaeocytes remember the whole body plan. The hydra has interstitial stem cells that divide continuously, replacing every cell in the body every few weeks, which is why a hydra shows no sign of ageing. The sea squirt can regenerate its whole body from a fragment of its blood vessels, using stem cells that circulate in the blood.

Insects use stem cells in ways that have no mammalian equivalent. A fruit fly has intestinal stem cells like a mammal, but it also has stem cells in its ovaries and testes that are controlled by the niche in a way that was first worked out in the fly, and the fly's germline stem cell niche is still the textbook example of how a niche works. A honeybee queen's ovaries contain stem cells that produce thousands of eggs a day for years, and a worker bee's ovaries are shut down by the queen's pheromones, which suppress the stem cells. The insect examples show that the stem cell and the niche are an ancient partnership, and that the same machinery is used to make eggs, blood, gut and skin across the animal kingdom.

Even the animals we think of as simple have stem cells that surprise us. The freshwater snail can regenerate its eye. The sea cucumber can eject its gut to distract a predator and regrow it. The octopus can regrow an arm, complete with suckers and nerves. The common thread is that regeneration is the ancestral condition in animals: the earliest animals could rebuild themselves, and the mammals are the exception, not the rule. Mammals traded regeneration for a different strategy, rapid wound closure with a scar, which stops bleeding and infection quickly but leaves the tissue imperfect. The study of animal stem cells is therefore also a study of what mammals lost, and whether it can be recovered.

Veterinary Uses

Stem cells are already used in veterinary medicine, and the horse was the first patient. Racehorses commonly injure their tendons, and a tendon heals slowly and weakly, which can end a horse's career. Since the early 2000s, veterinarians have treated tendon injuries with mesenchymal stem cells, usually taken from the horse's own bone marrow or fat, grown in the laboratory and injected into the injured tendon. The cells are thought to reduce inflammation and to encourage the tendon to heal with better organised tissue, and many horses have returned to racing after treatment. The evidence is still limited, with few controlled trials, but the treatment is widely used, and it is the most established veterinary stem cell therapy.

Dogs are the second patient. Adipose-derived mesenchymal stem cells, taken from a dog's own fat, are used to treat osteoarthritis, the wearing of the joints that cripples old dogs. The cells are injected into the joint, where they are thought to reduce inflammation and to protect the cartilage, and many owners report that their dogs move more easily and need less pain relief. The evidence is again limited, with small trials and much of it uncontrolled, and the effect is modest rather than a cure. Cats are treated experimentally for chronic kidney disease, a common and fatal condition, with stem cells injected into the kidney or the bloodstream, and early results suggest some improvement in kidney function, but the treatment is still experimental.

The veterinary field is honest about its limits. Most veterinary stem cell treatments are offered as options rather than proven cures, and the evidence for many of them is thin. The treatments are also expensive, which limits them to valuable animals, racehorses and pets whose owners can pay. The value of the veterinary work is therefore not only in the treatments themselves, but in what they teach: the horse and the dog are large animals with long lives, and what is learned from treating them is directly relevant to treating people. The veterinary clinic is, in this sense, a testing ground for human stem cell medicine.

Conservation Uses

Stem cells are now part of conservation, and the most famous case is the northern white rhinoceros. Only two females remain, Najin and her daughter Fatu, and the last male, Sudan, died in 2018, so the subspecies cannot breed naturally. The BioRescue project, working with the San Diego Zoo's Frozen Zoo, is making embryos from the banked cells of dead rhinos: skin cells from the frozen collection are turned into iPSCs, and the iPSCs are turned into eggs and sperm, which are then used to make embryos that will be carried by southern white rhino surrogates. The first embryos have already been made from eggs collected from Fatu and sperm from dead males, and the work is now moving towards the stem-cell step, which would widen the genetic pool beyond the few animals whose eggs can still be collected.

The same idea is being applied to other species. The black-footed ferret, once thought extinct, was brought back from eighteen animals, and in 2020 a clone named Elizabeth Ann was born from cells frozen in 1988 from a ferret named Willa, adding genetic diversity that the living population had lost. The Tasmanian devil, threatened by a contagious facial tumour, is being studied with stem cells and genomics to understand the disease and to preserve the species' genetic diversity. The Frozen Zoo in San Diego holds the cells of more than a thousand species, and the hope is that stem cell technology will let conservationists rebuild genetic diversity that would otherwise be lost forever.

The conservation use of stem cells is honest about its limits. A stem cell cannot bring back a species on its own: it can make an embryo, but the embryo needs a surrogate, a habitat, and a population to join, and a species reduced to a handful of individuals carries the genetic problems of inbreeding whatever technology is used. The technology is also expensive, and it can distract from the cheaper and more effective work of protecting habitats and stopping poaching. Stem cells are a tool for the last resort, for species that have already lost the numbers to recover on their own, and they work best when they are combined with the ordinary work of conservation, not offered as a substitute for it.

Limits, Risks and Tumours

The greatest risk of stem cells is the one that follows directly from their power. A pluripotent cell can become any tissue, and if it is placed in the body before it has been fully differentiated, it can form a teratoma, a tumour containing a jumble of tissues from all three germ layers: bone, hair, gut lining and nerve tissue, growing together in a disorganised mass. Teratomas are the reason that no pluripotent stem cell is ever transplanted as it is, and the reason that every stem cell product is tested for undifferentiated cells before it is used. The test is strict, because a single undifferentiated cell can, in principle, seed a tumour.

A second risk is immune rejection. A stem cell product made from one animal and given to another is recognised as foreign and attacked, just as an organ transplant is. The rejection can be avoided by using the patient's own cells, which is one of the main attractions of iPSCs, or by matching the donor and the recipient, or by suppressing the immune system, which carries its own risks. The rejection problem is smaller for some tissues than for others: the eye and the brain are partly protected from the immune system, which is why the first stem cell trials were in the eye, while the blood and the skin are fully exposed.

A third risk is the cancer stem cell. Many tumours contain a small population of cells that behave like stem cells: they divide slowly, resist chemotherapy, and can rebuild the tumour after treatment. The cancer stem cell hypothesis, first shown clearly in leukaemia, explains why some cancers return after treatment that seemed to work: the drugs kill the bulk of the tumour but spare the cancer stem cells, which then regrow it. The hypothesis is still debated, and not every tumour has cancer stem cells, but it has changed how cancer is studied, and it is one reason that stem cell biology and cancer biology are now closely linked.

The fourth risk is the unproven clinic. Stem cell treatments are sold around the world for conditions they cannot treat, from autism to ageing, by clinics that charge large sums for injections of cells whose identity and safety are unknown. The injections have caused tumours, infections and deaths, and the regulatory authorities in most countries warn against them. A genuine stem cell treatment is given in a hospital, as part of a trial or an approved therapy, with the cells fully characterised and the patient followed up. A treatment sold without evidence, without regulation and without follow-up is not medicine, and the stem cell field is unusually clear about saying so.

Ethics in Plain Language

The ethics of stem cells turn on one question: where do the cells come from? Embryonic stem cells come from embryos, and the use of human embryos for research is the most contested part of the field. The embryos used are surplus embryos from IVF treatment, donated with consent, which would otherwise be discarded, and the research is limited in most countries to the first fourteen days of development, before the nervous system begins to form. The fourteen-day rule is a compromise: it allows research on the earliest embryo, when the cells are most useful, and it draws a line before the embryo develops the structures that most people associate with a person. Some countries have extended the limit, and the international guidelines were revised in 2021 to allow case-by-case review beyond fourteen days, but the debate continues.

Animal embryos raise fewer objections, and most of the research in this article is done on animals, but animals raise their own questions. Stem cell research uses mice, and the mice are killed to obtain their cells and to test the treatments. The work is governed by the three Rs: replace animals where possible, reduce the number used, and refine the procedures to cause the least suffering. The question is not whether animals should be used at all, but whether the suffering is justified by the knowledge gained, and whether the same knowledge could be gained another way. The organoid, the miniature organ grown from stem cells in a dish, is one answer: it lets researchers study a gut, a brain or a retina without using an animal at all.

iPSCs have changed the ethical landscape, because they remove the embryo from the equation. A pluripotent stem cell can now be made from a skin sample, with the donor's consent, and the cells carry the donor's genes, which raises a different question: who owns the cells, and what may be done with them? A cell line made from a person's skin can be grown forever, shared with laboratories around the world, and used to make tissues that carry that person's genes. The consent given for a skin sample is therefore not a small matter, and the governance of iPSC banks, the collections of cell lines held for research and treatment, is now a live ethical question. The field has moved from the ethics of the embryo to the ethics of the donor, and the consent form has become as important as the laboratory protocol.

Key Takeaways

• A stem cell is defined by two abilities: self-renewal, making more stem cells, and differentiation, making specialised cells such as muscle, nerve, skin or blood.
• Potency forms a ladder: totipotent cells make a whole organism, pluripotent cells make every body cell type, multipotent cells make one lineage, and unipotent cells make one cell type.
• Embryonic stem cells come from the inner cell mass of the blastocyst and are pluripotent; adult stem cells live in niches in the bone marrow, gut, skin and muscle and are multipotent or unipotent.
• Induced pluripotent stem cells are made by reprogramming adult cells with four factors, Oct4, Sox2, Klf4 and c-Myc, and they remove the need for embryos.
• Haematopoietic stem cells in the bone marrow make every blood cell and are the basis of bone marrow transplantation, the oldest stem cell therapy.
• The gut renews every few days from Lgr5 stem cells in the crypts, the skin every few weeks from basal and bulge stem cells, and muscle from satellite cells after injury.
• Planarian neoblasts and the axolotl blastema show what regeneration looks like: mammals repair with a scar, while these animals rebuild without one.
• Stem cells are used in veterinary medicine for horses and dogs, and in conservation for the northern white rhino and the black-footed ferret, but the evidence is still limited and the work is expensive.
• The risks are teratomas from undifferentiated pluripotent cells, immune rejection, cancer stem cells, and unproven clinics selling treatments without evidence.
• The ethics turn on the source of the cells: embryonic stem cells use surplus IVF embryos under the fourteen-day rule, while iPSCs raise questions of donor consent and ownership.

Short Questions

1. What is a stem cell in simple words?

See answer

A stem cell is an unspecialised cell that can do two things no ordinary cell can. First, it can copy itself to make more stem cells, which is called self-renewal, so the supply never runs out. Second, it can produce daughter cells that specialise into particular cell types, such as a red blood cell, a skin cell, a muscle fibre or a neurone, which is called differentiation. Every animal begins as a single cell that divides into stem cells, and the stem cells that remain in the adult keep the blood, gut, skin and muscle supplied for a lifetime. A stem cell is therefore best thought of as a blank cell with a future still open.

2. What is the difference between totipotent and pluripotent?

See answer

A totipotent cell can make a complete organism, including the extra-embryonic tissues such as the placenta, while a pluripotent cell can make every cell type of the body but not the extra-embryonic tissues. Only the fertilised egg and the cells of the very early embryo, up to the eight-cell stage in mammals, are totipotent, and each of them could in principle develop into a whole animal, which is how identical twins arise. The embryonic stem cells of the inner cell mass are pluripotent: they can become a neurone, a muscle fibre, a blood cell or a gut cell, but they cannot make a placenta on their own. Pluripotency is therefore one rung below totipotency on the ladder of what a cell can become.

3. How are iPSCs made?

See answer

Induced pluripotent stem cells are made by reprogramming an adult cell, usually a skin fibroblast, with four genes called the Yamanaka factors: Oct4, Sox2, Klf4 and c-Myc. The four genes are transcription factors that switch other genes on and off, and together they reset the cell's identity, erasing the marks of its adult life and restoring the open genome of an embryonic cell. The method was discovered by Shinya Yamanaka in 2006 in mice and in 2007 in human cells, and it earned him the Nobel Prize in 2012. Because iPSCs are made from a skin or blood sample, they need no embryo, and they carry the donor's own genes, which makes them useful for studying disease and for personalised medicine.

4. Why can a planarian regrow its whole body but a human cannot regrow a limb?

See answer

A planarian can regrow its whole body because about a fifth to a third of its cells are neoblasts, pluripotent adult stem cells that can make every cell type the worm has. When the worm is cut, the neoblasts gather at the wound, divide, and rebuild whatever is missing, reading the body's positional signals to know whether to make a head or a tail. A human has stem cells too, but they are restricted: the blood stem cells make only blood, the skin stem cells make only skin, and there is no pluripotent stem cell in the adult human body and no blastema to rebuild a limb. Instead, a human wound is closed quickly with a scar, which stops bleeding and infection but does not restore the original structure. The difference is not the absence of stem cells, but what the stem cells are allowed to do.

5. What are haematopoietic stem cells and why do they matter in medicine?

See answer

Haematopoietic stem cells are the stem cells of the bone marrow that make every blood cell: the red cells that carry oxygen, the white cells that fight infection, and the platelets that clot the blood. A human makes hundreds of billions of blood cells every day, and all of them descend from a small number of these stem cells. They matter in medicine because they are the basis of bone marrow transplantation, the oldest stem cell therapy, in which a patient's diseased blood system is replaced with a donor's stem cells to treat leukaemia, lymphoma, immune deficiencies and inherited blood disorders. The first successful transplants were done in the late 1950s and 1960s, and the treatment earned E. Donnall Thomas the Nobel Prize in 1990.

6. Why are stem cells a tumour risk?

See answer

Stem cells are a tumour risk because the same properties that make them useful also let them grow without control. A pluripotent cell can become any tissue, and if it is transplanted before it has been fully differentiated, it can form a teratoma, a tumour containing a jumble of tissues from all three germ layers, such as bone, hair and gut lining. A second risk is the cancer stem cell: many tumours contain a small population of cells that behave like stem cells, divide slowly, resist chemotherapy, and rebuild the tumour after treatment, which is one reason some cancers return. For both reasons, no pluripotent stem cell is ever transplanted as it is: the cells are first differentiated in the dish, tested for undifferentiated cells, and only the differentiated cells are used.

Frequently Asked Questions

What are stem cells in animals in simple words?

Stem cells are unspecialised cells that can do two things no ordinary cell can: they can copy themselves to make more stem cells, which is called self-renewal, and they can produce daughter cells that specialise into particular cell types, such as muscle, nerve, skin or blood cells, which is called differentiation. Every animal begins as a single cell that divides into stem cells, and the stem cells that remain in the adult keep the blood, gut, skin and muscle supplied for a lifetime. A stem cell is best thought of as a blank cell with its future still open.

Are stem cells the same as embryonic cells?

No, embryonic cells are only one kind of stem cell. Embryonic stem cells come from the inner cell mass of the blastocyst and are pluripotent, able to make every cell type of the body. Adult stem cells are a different kind: they live in the bone marrow, gut, skin and muscle, and they are multipotent or unipotent, able to make only the cells of their own tissue. A third kind, the induced pluripotent stem cell, is made in the laboratory by reprogramming an adult cell, and it is pluripotent like an embryonic stem cell but needs no embryo. All three are stem cells, because all three self-renew and differentiate, but they differ in potency and in where they come from.

Can stem cells cure diseases in animals?

Stem cells can treat some diseases and not others. The proven treatment is bone marrow transplantation, in which haematopoietic stem cells replace a diseased blood system to treat leukaemia, lymphoma and some inherited blood disorders, and it has been used for decades. Skin stem cells are used to grow epidermis for burns, and mesenchymal stem cells are used in horses and dogs for tendon injuries and arthritis, although the evidence there is limited. Most other claimed cures are unproven: stem cells cannot yet regrow a damaged spinal cord, cure diabetes or reverse ageing, and treatments sold for such conditions by unregulated clinics have caused tumours, infections and deaths. A genuine stem cell treatment is given in a hospital, as part of a trial or an approved therapy, with the cells fully characterised.

Do all animals have stem cells?

Yes, all animals have stem cells, because every animal begins as a single cell that must divide and specialise to build a body. The simplest animals have the most powerful stem cells: a sponge's archaeocytes can make every cell type in the sponge, and a hydra's interstitial stem cells renew its whole body continuously. In complex animals the stem cells are more restricted: a mammal's blood stem cells make only blood, and its skin stem cells make only skin. The difference between animals is therefore not whether they have stem cells, but how much potency their stem cells keep and what they are allowed to rebuild.

Why can't humans regrow limbs like axolotls?

Humans cannot regrow limbs because their adult stem cells are restricted and their wounds heal with a scar instead of a blastema. An axolotl regrows a limb by forming a blastema, a mound of cells at the stump that have dedifferentiated back to a stem-like state and then redifferentiate into bone, muscle, skin, nerve and blood vessels in the right pattern. A human wound is closed quickly with scar tissue, which stops bleeding and infection but does not restore the original structure, and no pluripotent stem cell exists in the adult human body to rebuild a limb. The difference is not the absence of stem cells, but what the stem cells are allowed to do and the signals that guide them.

Are stem cell treatments for pets safe?

Some veterinary stem cell treatments are reasonably safe and others are experimental, and the difference matters. Mesenchymal stem cells from a dog's own fat, used for osteoarthritis, and from a horse's own bone marrow, used for tendon injuries, are generally well tolerated, because the cells come from the animal itself and are injected into a joint or a tendon. The evidence that they work is limited, with small trials and much of it uncontrolled, and the effect is modest rather than a cure. Treatments for other conditions, such as chronic kidney disease in cats, are still experimental. A treatment is safest when it is given by a veterinarian, uses the animal's own cells, and is offered as an option with honest limits rather than as a guaranteed cure.

Related reading

• Cell Membrane Structure and Function
• Mitochondria: The Powerhouse of the Cell
• Histology of Animal Tissues: Types and Step-by-Step Process

MCQs

1. What are the two defining properties of a stem cell?

• A. Self-renewal and differentiation
• B. Division and death
• C. Movement and feeding
• D. Growth and ageing

Answer: A

Explanation: A stem cell is defined by self-renewal, copying itself to make more stem cells, and differentiation, producing daughter cells that specialise into particular cell types.

2. Which of these cells is totipotent?

• A. Muscle satellite cell
• B. Skin stem cell
• C. Zygote
• D. Red blood cell

Answer: C

Explanation: The zygote is totipotent, because it can make a complete organism including the extra-embryonic tissues such as the placenta, while the other options are specialised or restricted cells.

3. How are induced pluripotent stem cells (iPSCs) made?

• A. By fusing two embryos together
• B. By reprogramming adult cells with four factors
• C. By freezing blood cells
• D. By cloning a whole animal

Answer: B

Explanation: iPSCs are made by introducing the four Yamanaka factors, Oct4, Sox2, Klf4 and c-Myc, into an adult cell such as a skin fibroblast, which resets it to pluripotency.

4. Where do haematopoietic stem cells live mainly?

• A. Bone marrow
• B. Liver
• C. Skin
• D. Brain

Answer: A

Explanation: Haematopoietic stem cells live in the bone marrow, where they make every blood cell: red cells, white cells and platelets.

5. The lining of the gut is renewed by stem cells in which structure?

• A. The tips of the villi
• B. The liver
• C. The acid-secreting cells of the stomach
• D. The crypts of Lieberkühn

Answer: D

Explanation: Intestinal stem cells sit at the base of the crypts of Lieberkühn, marked by the protein Lgr5, and their daughters move up the villus, differentiate and are shed within days.

6. Planarian regeneration depends mainly on which cells?

• A. Blood-clotting cells
• B. Neoblasts
• C. Nerve cord cells
• D. Shell-forming cells

Answer: B

Explanation: Neoblasts are the pluripotent adult stem cells of the planarian, making up about a fifth to a third of its cells, and they rebuild whatever part of the body is missing.

7. Which animal regrows a whole limb from a blastema?

• A. Mouse
• B. Sparrow
• C. Axolotl
• D. Adult frog

Answer: C

Explanation: The axolotl regrows a whole limb by forming a blastema, a mound of dedifferentiated cells at the stump that grows and redifferentiates into bone, muscle, skin, nerve and blood vessels.

8. The teratoma risk of stem cells is linked to which property?

• A. Pluripotent cells forming mixed tissues from all three germ layers
• B. Adult skin cells dividing slowly
• C. Red blood cells carrying oxygen
• D. Bone cells making calcium

Answer: A

Explanation: A teratoma is a tumour containing tissues from all three germ layers, and it forms when undifferentiated pluripotent cells are placed in the body, which is why stem cells are always differentiated before transplantation.

9. Which of these is one of the Yamanaka factors?

• A. Insulin
• B. Haemoglobin
• C. Collagen
• D. Oct4

Answer: D

Explanation: Oct4 is one of the four Yamanaka factors, together with Sox2, Klf4 and c-Myc, that reprogram an adult cell into an induced pluripotent stem cell.

10. In conservation, stem cells are used for the northern white rhino mainly to do what?

• A. Clone adult rhinos in zoos
• B. Make embryos from banked cells
• C. Grow replacement horns
• D. Change the rhino's DNA

Answer: B

Explanation: With only two females left and no living male, the BioRescue project turns banked skin cells into iPSCs and then into eggs and sperm to make embryos, which will be carried by southern white rhino surrogates.