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Stem cells and kidney repair

by Professor Malcolm R. Alison DSc, FRCPath

What are stem cells?

Stem cells are relatively primitive cells that can be stimulated to produce large families of cells that can then be instructed by chemical cues to produce various types of specialised cells, e.g. kidney tubular cells. The first stem cell therapies were with bone marrow stem cells, and bone marrow transplants for patients with the likes of leukaemia are now a standard hospital treatment. Likewise, skin transplants (grown from stem cells) are now ‘routine’ for burns patients. These bone marrow and skin transplants make use of adult stem cells, and these cells are said to be multipotential, capable of producing the limited range of cell types appropriate for their location. In many organs, including the kidney, the identity of stem cells has proved elusive, thus our ability to isolate and expand them for therapies has been severely compromised.

However, 1998 saw the publication of two scientific papers describing the growth in culture of human embryonic stem (ES) cells derived from very early (first 14 days) surplus embryos. The attraction of these cells is their amazing flexibility; using naturally occurring body chemicals, scientists can expand their numbers and make them become almost any one of the body’s over 200 cell types – a property known as pluripotentiality (pluri – L. many). The realisation of such pluripotentiality has, of course, resulted in the field of stem cell research going into overdrive and ‘Regenerative Medicine’ is fast becoming a branch of Hospital Medicine as familiar as say ‘Urology’ or ‘Renal Medicine’.

ES cell lines are invariably derived from the inner cell mass (ICM) of 5-day-old embryos called blastocysts (Figure 1). Blastocysts are usually ‘spares’ from in vitro fertilization (IVF) programmes that would have otherwise been discarded, though some have been deliberately created. These blastocysts are composed of about 100 cells, of which 30-40 make up the ICM. Specialised cells derived from ES cells have not yet reached clinical trials because most ES cells have been grown in the presence of animal products such as bovine (cow) serum, but ES cells can be grown without these products, conforming to ‘good manufacturing practice (GMP) conditions, so clinical trials are very much on the horizon. In the UK, the Human Fertilization and Embryology Authority (HFEA: http://www.hfea.gov.uk) licences and monitors all human embryo research, including using embryos for stem cell extraction. Moreover, on May 19th 2004 the world’s first stem cell bank opened in the UK, jointly overseen by the MRC and BBSRC (http://www.ukstemcellbank.org.uk/), acting as a repository and supplier of all types of human stem cells, not just embryonic but also those derived from foetal and adult tissues and discarded cord blood.

Figure 1
Figure 1. Scheme for the generation of new cells and tissues from embryonic stem cells. ES cells are often cultured upon a lawn of animal feeder cells that provide growth factor support for the expanding ES cells. Appropriate manipulation of the culture results in the formation of embryoid bodies, and a defined chemical cocktail can orchestrate differentiation towards a specific cell fate.

Of course, for ES cells to have a major impact on regenerative medicine, the transplanted cells, like whole organ transplants, must overcome the obstacles posed by immune system incompatibility (graft rejection). Somatic cell nuclear transfer (also called ‘therapeutic cloning’) offers the possibility of using the patient’s own genetic material to generate ES cells and so overcome this problem (Figure 2). Therapeutic cloning (‘Dolly’ technology) involves taking an adult cell from the patient and inserting it into an enucleated egg from an anonymous female donor (not as easy as it sounds), nurturing it to the blastocyst stage and then harvesting the ES cells from the ICM. Each cell would be almost identical in genetic terms to the cells of the patient who would be treated with them.

The recent controversy regarding human-animal hybrids (so-called ‘human admixed embryos’) stems from a desire to understand how adult stem cells are reprogrammed back to this pluripotential embryonic state by putting an adult human nucleus into, for example, a cow’s egg; there is a real shortage of donated human eggs (oocytes) to carry out this vital research. However, no cells for therapeutic use would be produced by this vexatious procedure.

In another big leap forward, over the last year, scientists in Kyoto, Japan seem to have bypassed even therapeutic cloning, have succeeded in making adult human cells ‘turn back the clock’ and become like ES cells, simply by culturing adult cells with 3 or 4 defined factors. This is no ‘flash in the pan’ as the results have been reproduced around the world, and these so-called ‘induced pluripotential stem (iPS) cells’ may make therapeutic cloning redundant.

Figure 2
Figure 2. ES cells are pluripotential, but during development, tissue-specific (TS) stem cells are laid down in individual organs that are multipotential, only giving rise to a limited range of cell types appropriate to their location. In the environment of the egg cytoplasm, nuclei from adult somatic cells can be reprogrammed back to ES cells (therapeutic cloning). Introducing 3-4 genes that are active in ES cells can also switch adult cells back to a pluripotent state.

Adult stem cells

As far as we know, all organs have specific stem cells, but in some tissues such as the heart and brain, they don’t generate new cells after cell loss caused by a heart attack or stroke. In the kidney, specialised tubular cells can proliferate to some extent to replace lost cells, but the ability to replaced whole nephrons has been lost, a property restricted to some bony and cartilaginous fish. In fact if you lose or donate a kidney, the remaining kidney functions perfectly well by initially responding to the loss by increasing by as much as 40% in size, largely achieved by the surviving cells getting bigger. So kidneys can respond appropriately to damage and regenerate, but often the damage is so severe that the structural framework of the kidney becomes distorted, such that normal regeneration is not possible leading to fibrosis and ‘end-stage’ renal disease. A cell therapy could be a possible treatment, as it could be for genetic diseases such as Alport’s and polycystic kidney disease where no amount of local regeneration will overcome the inherited defect. Apart from ES cells, other sources of malleable stem cells include cells from umbilical cord blood, bone marrow, amniocentesis fluid and even liposuction waste! All these cells can be manipulated in culture to become various types of specialised cells, a feature called ‘stem cell plasticity’. Perhaps the most attractive of all these cell sources are bone marrow cells as these can be readily harvested from the patient or another donor. The NHS is already funding clinical trials exploring the potential benefits of the injection of a patient’s own bone marrow cells into the area surrounding heart muscle damage after a heart attack. Similar studies are being carried out in animal models of kidney damage with encouraging results, although the beneficial effects of the injected cells may not be directly related to their conversion to kidney cells, but may have more to do with the fact that either the vasculature is improved in the damaged kidney or the administered cells release growth factors that promote the regeneration of the indigenous renal cells. Similar mechanisms may underlie the benefits of bone marrow cell therapy for patients with cardiovascular disease. An alternative to bone marrow cell injection may be their induced mobilization into the bloodstream that would facilitate their ‘homing’ to the acutely damaged kidney; this procedure is already widely adopted when there is a need to ‘bank’ a proportion of a cancer patient’s bone marrow stem cells prior to chemotherapy, a procedure that might otherwise dangerously deplete these valuable blood cells.

What renal diseases may benefit from stem cell therapy?

The kidney is a complex organ with over 30 different cell types, and present technology does not envisage constructing a whole kidney from stem cells. However, within existing kidneys where the basic scaffolding is intact, stem cells may contribute to a variety of specialised cell types, either promoting more efficient repair or correcting genetic defects. These would include

  1. acute tubular necrosis (ATN) caused by toxins or ischaemia/reperfusion (associated with kidney transplantation);
  2. mesangial damage, often associated with immune complex deposition and diabetes;
  3. defective podocyte function (Alport’s disease); and
  4. vascular endothelial damage (e.g. in glomerulonephritis).

In this article I have reviewed the potential benefits of ES cells, iPS cells and other malleable stem cells for kidney repair. According to recent statistics over 5,000 patients in the UK are on the kidney transplant waiting list, so stem cell therapies using either embryonic or adult stem cells may be part of the solution to the long waiting lists worldwide.

The National Kidney Federation cannot accept responsibility for information provided. The above is for guidance only. Patients are advised to seek further information from their own doctor.

NKF Controlled Document No. 216: Stem cells and kidney repair written: 27/03/2008 last reviewed: 27/03/2008