Telomere attrition in hemopoietic stem cells begins immediately after birth

While stem cells exhibit the capacity to differentiate and self- renew, their ability to do so is now known to decline with age. The stem cell niche plays a key role in this decline, particularly in the case of embryonic stem cells. At the level of individual cells, replicative capacity is to reason that telomere dynamics should be intimately involved with this age-related decline in stem cell function. To this end, Holmes et al. have recently investigated telomere dynamics in a longitudinal study of fetal and early post-natal subjects:

Telomere length dynamics differ in foetal and early post-natal leukocytes in a longitudinal study

Haemopoietic stem cells (HSC) undergo a process of self renewal to constantly maintain blood cell turnover. However, it has become apparent that adult HSC lose their self-renewal ability with age. Telomere shortening in peripheral blood leukocytes has been seen to occur with age and it has been associated with loss of HSC proliferative capacity and cellular ageing. In contrast foetal HSC are known to have greater proliferative capacity than post-natal stem cells. However it is unknown whether they undergo a similar process of telomere shortening. In this study we show a more accentuated rate of telomere loss in leukocytes from pre term infants compared to human foetuses of comparable age followed longitudinally for 8-12weeks in a longitudinal study. Our results point to a difference inHSC behaviour between foetal and early postnatal life which isindependent of age but may be influenced by events at birth itself.

To compare telomere dynamics between fetal and adult stem cells, theauthors carried out a longitudinal analysis of peripheral blood. Obtaining serial fetal samples from healthy subjects would be fraught with ethical issues, hence alloimmune fetuses (AF) undergoing intrauterine transfusion were utilized. Venous samples from age-matched fetuses undergoing termination of pregnancy (TOP) for non-hematological reasons served as controls; no significant differences in terms of MNC behavior were noted, hence the AF samples were considered to be representative.

MNC telomere length in the AF samples was then compared with pre-term infants (PTI) of equivalent gestational age to assess the impact of the different environments (in utero vs. post-natal). In 7 of the 8fetal samples, comparison between the first and last serial samples revealed either an increase in mean telomere length, or no “detectable“ change in length (overall, the average gain in length was 19 bp/week). A similar analysis was performed on the PTI samples with equivalent gestational ages; in contrast to the fetal samples, 4 out of 5 PTI samples demonstrated considerable age-related telomere length decline (238bp/week). No significant changes in sub-sets of peripheral blood cells occurred between time points or between AF and PTI groups.

The paper supports the notion that stem cells lose efficacy with increasing age — even very early age. Furthermore, regarding the environmental influence on stem cell efficacy, these data extend the scope of the term “environment” beyond the stem cell niche and into the macroscopic world: in utero, fetuses continue to extend their telomeres — even though their cells are rapidly dividing –whereas once they are ex utero, babies start to shorten their telomeres.

During the discussion, the authors suggest that “different mechanisms of telomere length maintenance operate…in foetal compared to post-natal life”. Unfortunately, these differences are not investigated further in this study. I would have liked to see the authors measure telomerase activity and correlate this with the differing rates of attrition. Furthermore, the physical weight of the PTI samples should be included: it is recognized that babies born small-for-gestation age (SGA) are prone to developing problems in adulthood (including hypertension), possibly as a result of increased growth (with concurrent telomere loss) during the first year of life. In light of this, omission of weight data makes the interpretation of the results less robust.

Leaving the mechanisms aside for the moment, the data indicate that fetal HSCs may provide a superior source of cells for use in the clinical setting — assuming, that is, that removing them from the in utero context isn’t the event that flips the switch from telomere elongation to telomere attrition.