Parent stem cells are the only ones that can renew themselves, forming at least one or, in many cases, various types of specialized cells.

The group of specialized cells produced by the original parent cell is called cell lineage. We must distinguish at least four types of parent cells:

a)Unipotent parent cells: these can produce only one cell type, ie. the spermatogonium that generates only one type of differentiated cell - the spermatozoid.

b) Multipotent parent cells: these can produce only one type of cell lineage, ie. the haemopoietic parent cells (or blood cells) which produce only haemopoietic cells (red blood cells and all types of white blood cells).

c) Pluripotent parent cells: these can generate various types of cell lineages, ie. embryonic parent cells, embryonic carcinoma cells, and embryonic germ cells. The latter will be dealt with further on.

d) Totipotent parent cells: these parent cells can generate all the body cells; only one cell can do this and it is the oosperm or the unicellular embryo.

Of the four types of parent cells described here, the second and third can be used to obtain various tissues and hence are those that are involved in cloning procedures1 .

Pluripotent cells
Since pluripotent parent cells can generate any cell type present in the human body, there could be the possibility of treating certain diseases that are caused by serious alterations of a certain tissue or organ. Theoretically, neurons and neuroglia could be produced to treat neurogenic diseases such as Parkinson’s or Alzheimer’s disease, muscle cells could be produced to treat muscular dystrophies and heart diseases, haemopoietic parent cells could be produced to treat various types of leukaemia and AIDS, and the list could go on. Pluripotent parent cells can be obtained from three sources:

a) starting from teratoid carcinomas or embryonic carcinomas: embryonic carcinoma cells (EC). Teratoid carcinomas are tumours that affect the gonads - their large tissular variety derives from the three cellular layers that form an embryo (endoderm, mesoderm and ectoderm)2 ,3 . These tumours present a large variety of tissues including cartilage, epithelium, primary neuroectoderm, ganglia, muscle, bone and glandular epithelium. Differentiated tumour cells are formed from pluripotent parent cells of embryonic carcinomas which derive, in turn, from primitive germ cells of the embryo after it is implanted (these are the embryonic precursors of the gametes) 4 , 5 . This type of parent cells (EC) are one of the main components of cancer in the male gonads. The parent cells (EC) have been cultivated in vitro by isolating them from tumours 6 , 7 , 8 , and it has been proved that certain tissue types can be obtained from them. Probably one of the most spectacular experiments was the one performed in 1998 in the US - one line of cells from an orchic tumour was treated in the lab with retinoic acid. This factor enabled scientists to produce nerve cells from the tumour cells that were implanted in rats, succeeding in regenerating cerebral damage. The experiment was repeated to treat a cerebral infarction (apoplexy) in a woman aged 62.

b) starting from human embryos: embryonic parent cells (ES). Embryonic parent cells are derived from the internal cellular layer of the embryo before implantation as a blastocyst 9 , 10 . All tissue types that form the human body can be obtained from these. There have been cell cultures of embryonic parent cells derived from rat blastocysts and from human (among other species) blastocysts. The cells thus cultivated seem able to remain in the cell culture for an indefinite period. Obtaining these embryonic parent cells and cultivating them in vitro in order to obtain various tissue types invariably leads to the death of the embryo. The ethical problem concerning the use of these embryonic parent cells as precursor biological material is based on this, because obtaining the tissue invariably leads to the death of the embryo.

c) starting from embryonic germ cells (EG). The EG derive from primitive embryonic germ cells after implantation. This type of parent cell can be obtained from tissues of aborted foetuses, just as Dr. Gearhart’s group recently did. 11 . According to what was published by Dr. Gearhart’s group, the EG cells in vitro, in the presence of serum and certain factors, cannot be morphologically distinguished from EC or EG cells.

Adult parent cells
As already mentioned, parent cells are not a cell type that is typical of embryos, but they can also be found in other tissues of the adult human body. These are the so-called multipotent parent cells or adult parent cells. Among these are the haemopoietic parent cells which produce all the blood cells, or the precursor cells of neurons and of neuroglia also called neuroblasts, or the parent cells of the basal layer of the epidermis, which can generate various epithelial cells etc. The main difference between the pluripotent parent cells derived from the embryo or the multipotent parent cells derived from an adult consists in the number of cell lineages that each can produce.

Till recent years, the idea that multipotent adult parent cells could produce only one cell lineage was widely accepted, while the pluripotent embryonic ones could generate various cell lineages. Recent studies prove that many multipotent cells can form a greater variety of cell types than scientists believed. For example we can mention some studies that were published in some of the most prestigious scientific magazines - they highlight how adult multipotent parent cells, in suitable conditions in vitro, can produce cell lineages that differ from what was expected. This is the case of the work published by the Vescovi group12 , which describes how, in rats, adult parent nerve cells can turn into blood cells. The plasticity or versatility typical of neuroblasts according to Vescovi’s study are not exclusive of this cell type. In fact, we find similar works in literature with mesenchymal cells13 which, as per the article published in Science, can be precursors of differentiated brain cells. Instead, the plasticity of mesenchymal cells is widely studied in the paper by researchers of the company Osiris Therapeutics and the John Hopkins University and which too was published in Science 14 . In March 2000, a research group in Philadelphia published an article which explained the great proliferation of bone marrow parent cells15 . This marked another step towards the clinical application of this type of adult parent cells. Another study which produced similar results was conducted by Dr. Ira Blank of the University of Medicine and Dentistry of New Jersey and by Darwin Prockop of the Hahnemann University of Philadelphia 16 . In June 2000 a study conducted by the Karolinska Institute in Stockholm was published in Science - it stated that adult rat nerve parent cells can produce various organs such as heart, muscle, liver, lungs and intestines.17 . It was thus proved that adult nerve parent cells have a greater development capacity than was previously believed and they could be potentially used to generate cell lineages for transplants. Furthermore, adult rat neurons have contributed to the formation of rat embryos, also generating stem cell lineages. In July 2000 two research teams in the US and in Great Britain proved that human bone marrow cells could generate hepatic tissue18 , 19 . In August 2000 a research team of the South Florida University proved that the versatility of haemopoietic parent cells is such that they can even turn into neurons. When human or rat bone marrow parent cells are cultivated in vitro with certain growth factors, they become immature nerve cells 20 . In December 2000 a study was published by a team of the Toronto Paediatric Hospital, Canada, which proved that there exist two types of parent cells in the blood - they differ in their survival period after transplant. Scientists called them repopulation of short and long term parent cells. Hence there are some cells that work only during the first month, to later disappear, and there are other cells that begin to work after a few months and never cease to do so from then onwards 21 . Another study, published in Nature Medicine 22 , proves that bone marrow adult parent cells can heal the heart damage that follows an infarction. Studies have also been published on the capacity of epithelial parent cells to generate nerve cells, neuroglia, smooth muscle cells and adipocytes 23 .

These examples may suffice to describe the terrific potential present in adult parent cells. At first it was thought that adult parent cells had a limited potential as concerns the production of differentiated cell lines. Till recent years, the scientific community was convinced that a multipotent parent cell could generate only cells of the tissue type it belonged to. Hence, haemopoietic parent cells could only produce cells of the blood; neuroblasts could only produce cells of the nervous system, and so on. Instead, the above specified experiments and others too have proved that the capacity of multipotent cells to generate different tissue types depends on their environment and the chemical factors that in a certain environment guide their differentiation. This fact explains why adult parent cells are more plastic (able to generate cells of various tissue types) than was supposed and those that have so far been called multipotent parent cells will probably soon belong to the pluripotent parent cells, which include embryonic parent cells. Subsequently adult parent cells can be extremely useful in the treatment of certain human diseases. It has been argued that adult parent cells (as compared to embryonic parent cells) cannot be kept indefinitely in a cell culture without losing their plasticity. However, recent studies have proved that a type of multipotent adult parent cell, the precursors of oligodendrocytes, can grow for an indefinite period when cultivated in vitro24 . These studies suggest that conditions can be established in which parent cells can grow for an indefinite time.

(translated by Interpres sas)

Mònica Lòpez Barahona
Professor of Cellular Biology, Molecular Oncology and Bioethics
Francisco de Vitoria University Madrid