Telomeres and replicative cellular aging of the human placenta and chorioamniotic membranes

Tsung-Po Lai,Utz Herbig,Jungsik Noh,Debra Heller,Mark Simpson,Jerry W Shay,George Guirguis,Simon Verhulst,Krunal Patel,Abraham Aviv,Natalie Roche

doi:10.1038/s41598-021-84728-2

Abstract

Recent hypotheses propose that the human placenta and chorioamniotic membranes (CAMs) experience telomere length (TL)-mediated senescence. These hypotheses are based on mean TL (mTL) measurements, but replicative senescence is triggered by short and dysfunctional telomeres, not mTL. We measured short telomeres by a vanguard method, the Telomere shortest length assay, and telomere-dysfunction-induced DNA damage foci (TIF) in placentas and CAMs between 18-week gestation and at full-term. Both the placenta and CAMs showed a buildup of short telomeres and TIFs, but not shortening of mTL from 18-weeks to full-term. In the placenta, TIFs correlated with short telomeres but not mTL. CAMs of preterm birth pregnancies with intra-amniotic infection showed shorter mTL and increased proportions of short telomeres. We conclude that the placenta and probably the CAMs undergo TL-mediated replicative aging. Further research is warranted whether TL-mediated replicative aging plays a role in all preterm births.

Highlights

Recent hypotheses propose that the human placenta and chorioamniotic membranes (CAMs) experience telomere length (TL)-mediated senescence
We propose that these ‘replicative aging’ hypotheses of the placenta and CAMs require revisions based on the following premise: The shortest telomeres[5,6], expressed in dysfunctional telomeres[7,8,9,10] and their buildup, rather than mean TL (mTL), are the indicators of telomere-mediated aging of the placenta and CAMs, as their biological utility draws to an end
Characteristics of TL parameters measured by Southern blotting (SB) and Telomere Shortest Length Assay (TeSLA), and telomere dysfunction meas‐ ured by telomere-dysfunction-induced DNA damage foci (TIF)

Summary

Introduction

Recent hypotheses propose that the human placenta and chorioamniotic membranes (CAMs) experience telomere length (TL)-mediated senescence These hypotheses are based on mean TL (mTL) measurements, but replicative senescence is triggered by short and dysfunctional telomeres, not mTL. We measured short telomeres by a vanguard method, the Telomere shortest length assay, and telomere-dysfunction-induced DNA damage foci (TIF) in placentas and CAMs between 18-week gestation and at full-term. We proceeded as follows to test this idea: First, we obtained samples at the end of normal (full term) pregnancies from the placenta, the CM and AM, UCB and maternal blood from mother-newborn pairs In these samples and all other samples collected in this study, we (a) measured the mean length of the terminal restriction fragments (TRFs), generated by Southern blotting (SB)[11], and (b) measured and tallied the TRFs by the newly-developed Telomere Shortest Length Assay (TeSLA)[12]. In a pilot study, we measured TL parameters by SB and TeSLA in placenta and CAMs at birth in (a) uneventful full-term

Methods

Results

Conclusion