Stem cells and cell potency

What makes a cell a stem cell

Almost every cell in the body is specialised for one function and does not change to another. A stem cell is an exception. It is unspecialised, and it keeps two abilities that a specialised cell has given up: it can divide by mitosis to produce more cells like itself, which is self-renewal, and it can differentiate into at least one specialised type.

Both properties are required, and questions distinguish them. A cell that could differentiate but not renew itself would be used up after one division and the tissue would have no means of replacing it. A cell that divided without limit and never differentiated would form a mass rather than a tissue, which is the link between this topic and loss of checkpoint control.

Stem-cell division supplies continuous tissue replacement. The epithelium lining the small intestine is replaced about every five days, and roughly two million erythrocytes are produced every second. None of that replacement comes from mature cells dividing, because a mature erythrocyte has no nucleus and a neurone has left the cell cycle permanently. It comes from stem cells within the tissue.

Stem cell

An unspecialised cell that can divide repeatedly to produce more cells like itself, and can differentiate into one or more specialised types.

Self-renewal

Division that produces at least one daughter cell identical to the parent stem cell, so the population of stem cells is maintained.

Differentiation

The process by which a cell becomes specialised, through transcription of some of its genes and not others.

Potency

The range of cell types a stem cell is still able to become.

The four levels of potency

Potency is examined by name. Learn the four terms with an example attached to each, and state what a given cell can and cannot produce.

Describe the drawing

Four boxes drawn one inside another, labelled from the outside in: totipotent, with a zygote as the example, able to become any cell type and the placenta; pluripotent, the inner cell mass of a blastocyst, able to become any cell type in the body but not the placenta; multipotent, a bone marrow stem cell, able to become any kind of blood cell; and unipotent, an erythroblast, able to become red blood cells only. Each set of fates is contained in the one outside it.

A totipotent cell can become every cell type of the organism and also the extra-embryonic tissues, which means the placenta and the membranes around the embryo. In a mammal that is the zygote and the cells of the first few divisions, and it does not last: within a few days no cell of a human embryo is totipotent any longer. Plants behave differently, and a single parenchyma cell from a carrot root can be grown into a whole carrot plant, which is why plant tissue culture works at all.

A pluripotent cell can become any cell type found in the body but not the extra-embryonic tissues, so it cannot by itself give rise to a whole organism. The standard example is a cell of the inner cell mass of a blastocyst, and an embryonic stem cell is exactly that cell grown in culture.

A multipotent cell can become a limited number of related types, usually the types belonging to one tissue. Quote the haematopoietic stem cells of bone marrow: they give rise to erythrocytes, to every kind of white blood cell, and to the megakaryocytes that shed platelets, and to nothing outside that family.

A unipotent cell can become one type only. The example exam papers use is the precursor that makes new heart muscle cells, though how much the adult heart renews itself, and from what, is still argued over in the research literature. The committed red cell precursor in the figure shows the same narrowing, with one correction attached: strictly it is a committed progenitor rather than a stem cell, dividing a limited number of times on its way to becoming red blood cells rather than maintaining its own population indefinitely.

Apply the term totipotent strictly. Unless the cell named in a question is a zygote or one of the small number of cells immediately descended from it, it is not totipotent.

Where stem cells are obtained from

Four sources appear in specifications, and each has an associated potency, a practical limitation and, in one case, an ethical debate. Learn them as a set, because comparison questions are common.

Describe the drawing

Four cards, one per source of stem cells. Embryonic stem cells come from the inner cell mass of a blastocyst about five days old and are pluripotent. Umbilical cord blood is taken from the cord at birth, then frozen and stored, and is multipotent. Adult tissue such as bone marrow, the gut lining, skin, the cornea and the brain gives multipotent cells. Induced pluripotent cells are made from an adult body cell given four transcription factors, and are pluripotent.

Embryonic stem cells are taken from the inner cell mass of a blastocyst about five days after fertilisation, in practice one produced by in vitro fertilisation and not returned to the uterus. They are pluripotent and divide in culture without an apparent limit, which gives them the widest range of applications on this list. The blastocyst does not survive the procedure, which is the source of the ethical debate set out below.

Umbilical cord blood is collected from the cord and placenta after a birth, which carries no risk to mother or infant, and can be frozen and stored for years. The cells are multipotent and mainly haematopoietic. The limitation is quantity: one cord yields a small volume, which may be too few cells to treat an adult.

Adult tissue holds small populations of multipotent cells in bone marrow, the lining of the gut, the skin, the cornea and the brain. Bone marrow is aspirated from the pelvis under anaesthetic, so the donor takes a small risk. These cells are hard to find and to separate from the tissue around them, and their range is narrow, but cells taken from a patient and returned to the same patient carry no antigens the patient's immune system will react against.

Induced pluripotent stem cells, usually written iPS cells, are the newest of the four. An ordinary body cell such as a skin fibroblast is given four genes coding for transcription factors (Oct4, Sox2, Klf4 and c-Myc), and those factors switch the cell's own genes back to the pattern of a pluripotent cell. The result is pluripotent, patient-specific and made without an embryo, which is relevant to the ethical argument set out below. The technique is still under investigation: reprogramming works on a small fraction of the cells treated, and early methods used a virus to carry the genes in, which raised the risk of tumours forming afterwards.

Potency narrows by changes in gene expression

Differentiation does not remove genes. Most nucleated somatic cells contain the same complete genome, and what differs between a neurone and a lymphocyte is which genes are transcribed. As a cell differentiates, groups of genes cease to be expressed and the regulatory state that would restore their expression is dismantled, so potency narrows while the DNA sequence is unchanged.

Describe the drawing

An adult body cell on the left, drawn as a circle with its nucleus, with an arrow to the right labelled four factors added. The arrow leads to an induced pluripotent stem cell of the same size, from which three further arrows lead to a neurone, heart muscle and a blood cell. Below, two panels compare the genome before and after: in the adult cell every gene is present with most switched off, and in the induced pluripotent cell exactly the same genes are present with different ones switched on.

Two pieces of evidence are usually cited. In 1996 a nucleus taken from an adult sheep's mammary gland cell was transferred into an egg cell whose own nucleus had been removed, and the result was a whole sheep. That nucleus had been sitting in a specialised cell, and it still held everything needed to build a lamb. Then in 2006 came reprogramming: four transcription factors were enough to return a mouse fibroblast to a pluripotent state, and human cells followed the year after. The four genes delivered are extra copies of genes the fibroblast already carried, there to reawaken the cell's own copies, which is why the figure can truthfully show the same gene list before and after.

Potency is therefore a property of gene regulation rather than of gene content, which is why it can be reversed. It also accounts for the nesting in the figure: each step inwards removes access to the expression programmes of the cell types no longer available. The relevant quantity is which programmes can still be reactivated, not the number of genes not currently expressed.

Established treatments and proposed applications

Three applications are established clinical treatments. A bone marrow transplant replaces a patient's haematopoietic stem cells and has been used since the 1960s for leukaemia and for inherited disorders of the blood and the immune system. Skin grafts for severe burns can be grown from a patient's own epidermal stem cells. Limbal stem cell grafts restore a cornea whose own stem cell population has been damaged, and restore sight with it.

Everything else on the usual list is a trial or a proposal. Insulin-secreting cells for type 1 diabetes, dopamine-secreting neurones for Parkinson's disease, retinal pigment cells for macular degeneration, repair after a spinal injury and repair of heart muscle after an infarction are all under investigation, and some have reached trials in patients. Describe a treatment at the stage it has reached: a trial in progress is not an established treatment.

There is also a use with no transplant in it. Cells carrying a genetic disorder can be reprogrammed, grown into the affected tissue, and used to study the disorder and to test drugs on human tissue rather than on an animal.

Name three difficulties: controlling differentiation so that only the required cell type is produced, the risk that undifferentiated cells left in the transplant form a tumour, and rejection by the immune system unless the cells came from the patient. Cost and trial duration can be added.

The argument about embryonic sources

Questions on this topic carry the command words evaluate and discuss, and require reasoning on each side followed by a conclusion that follows from that reasoning. The positions below are set out without adjudication between them.

One position is that a human embryo is a human individual from fertilisation onwards, and that its development may not be ended for the benefit of another person, whatever that benefit. On this view the number of cells and the absence of a nervous system are not relevant, because the relevant consideration is what the embryo is and what it will become.

A second position is that moral status is acquired gradually. A blastocyst is about a hundred cells with no nerve tissue and no capacity to feel anything, and even in normal reproduction a large proportion of embryos never implant. On this view its claim is real but weaker than the claim of a person living with an untreatable condition.

A third argument concerns the embryos actually used. They are typically surplus from in vitro fertilisation, produced with consent and destined otherwise to be allowed to perish, so the argument runs that research adds no loss that was not going to happen. Two replies are made to it: that consenting to one outcome does not by itself make a different use permissible, and that a demand for embryos may encourage the production of more of them than a couple needs.

A fourth position is about regulation rather than principle. In the United Kingdom research on human embryos requires a licence from the Human Fertilisation and Embryology Authority, requires the consent of the donors, and may not continue beyond fourteen days after fertilisation, which is when the primitive streak appears and the point after which twinning can no longer occur. Some hold that a regulated limit is where a line can reasonably be drawn; others hold that any line drawn at a developmental landmark is arbitrary, and countries differ on where they have drawn it.

A fifth argument is that the question is being overtaken. If iPS cells can do what embryonic cells do, then an embryonic source is no longer necessary. Against that, iPS cells have not yet been shown to be equivalent: embryonic lines are still the standard they are compared with, reprogramming carries its own risk of tumours, and the comparison itself requires embryonic cells to exist.