The blood-forming or hematopoietic system is and has been
extensively studied for a variety of reasons. It represents the
prototype of a self-renewing biological system in that large
numbers of blood cells have to be produced daily in order to
compensate for the loss of relatively short-lived mature blood
cells. The relative ease at which blood and bone marrow
samples can be obtained and single cell suspensions prepared
has greatly facilitated in vitro and in vivo experimentation with
hematopoietic cells. Monoclonal antibodies specific for a
variety of cell surface antigens expressed on hematopoietic
cells have been produced and techniques to separate cells using
combinations of such reagents have been developed. A large
number of molecules with activity on various hematopoietic
cells are now available as are various in vitro assays to measure
functional properties of hematopoietic cells.
The hematopoietic system has been subdivided into a
hierarchy of three distinct populations (Till et al., 1964;
Metcalf, 1984). In this model the most mature cells are mor-
phologically identifiable as belonging to a particular lineage
and have very limited proliferative potential. The cells in this
most mature compartment are derived from committed prog-
enitor cells with a higher but still finite proliferative potential.
Committed progenitor cells in turn are produced by a popula-
tion of multipotential hematopoietic stem cells with self-
renewal potential, i.e. the capacity to give rise to more cells
with indistinguishable properties and developmental potential.
Self-renewal of stem cells is believed to be essential for main-
tenance of hematopoiesis over time.
Studies with cultured hematopoietic cells have shown that the
formation of hematopoietic colonies as well as the proliferation
and survival of various hematopoietic cells typically requires
the presence of ‘hematopoietic growth factors’, many of which
have been cloned over the last decade (Metcalf, 1989, 1993).
Many investigators have interpreted these observations as
evidence that the behavior of hematopoietic cells is ultimately
controlled by extracellular signals. This notion, together with
the possibility of purifying various hematopoietic cells with
unprecedented precision has led to frantic research efforts over
the last five years to achieve clinical useful manipulation of
blood-cell production in vitro. Two sets of observations cast
doubt about the feasibility of some of these perceived applica-
tions in the short term. First, there are a number of observations
indicating that extracellular factors do not appear to control
lineage commitment and self-renewal but instead seem to
permit exhibition of a predetermined cellular proliferative and
differentiation potential (Ogawa, 1989; Lansdorp et al., 1993;
Mayani et al., 1993). These findings suggest that the decisions
that ultimately determine the fate of hematopoietic stem cells
are not dictated by the environment but instead are controlled
by currently ill-defined, intrinsic genetic mechanisms with a
developmental component. A second hurdle to meaningful in
vitro stem cell ‘expansion’ is the observation that hematopoi-
etic cells, including purified hematopoietic stem cells, appear to
loose telomeric DNA with each cell division and with age
(Vaziri et al., 1994). This Commentary is focused on the role
of telomeres and telomerase in normal and abnormal
hematopoietic cells. As telomerase activity has so far not been
found in any somatic tissues (Counter et al., 1994), the findings
in the hematopoietic system appear to be applicable to other
self-renewing somatic tissues as well. More extensive and
general reviews on telomeres and telomerase have been
published elsewhere (Blackburn, 1991, 1992; Harley, 1991).
STRUCTURE AND FUNCTION OF TELOMERES
Without extremely reliable mechanisms to duplicate and
Telomere length and proliferation potential of hematopoietic stem cells
Peter M. Lansdorp
Terry Fox Laboratory, British Columbia Cancer Agency, 601 West 10th Avenue, Vancouver, BC, Canada V5Z 1L3
Journal of Cell Science 108, 1-6 (1995)
Printed in Great Britain © The Company of Biologists Limited 1995
Hematopoietic stem cells have typically been defined as
pluripotent cells with self-renewal capacity. Recent studies
have shown striking differences in the mean length of
telomeric repeat sequences at the end of chromosomes from
human hematopoietic cells at different stages of develop-
ment. The most likely explanation for these observations is
that hematopoietic stem cells, like all other somatic cells
studied to date, lose telomeric DNA upon each cell division.
In this review, limitations in the replicative potential of
hematopoietic stem cells are discussed in the context of
possible clinical use of such cells for transplantation and
Key words: telomeric DNA, proliferative potential, self-renewal,
hematopoietic stem cell
Till, J. E., McCulloch, E. A. and Siminovitch, L. (1964). A stochastic model
of stem cell proliferation, based on the growth of spleen colony-forming
cells. Proc. Nat. Acad. Sci. USA 51, 29-36.
Vaziri, H., Schachter, F., Uchida, I., Wei, L., Zhu, X., Effros, R., Cohen, D.
and Harley, C. B. (1993). Loss of telomeric DNA during aging of normal
and trisomy 21 human lymphocytes. Am. J. Hum. Genet. 52, 661-667.
Vaziri, H., Dragowska, W., Allsopp, R. C., Thomas, T. E., Harley, C. B. and
Lansdorp, P. M. (1994). Evidence for a mitotic clock in human
hematopoietic stem cells: loss of telomeric DNA with age. Proc. Nat. Acad.
Sci. USA 91, 9857-9860.
Watson, J. D. (1972). Origin of concatameric T4 DNA. Nature New Biol. 239,
P. M. Lansdorp