Digging deeper into the mysteries of miscarriage: micromanaging the interaction between conceptus and endometrium

Frustration and futility are arguably no better defined in the human condition than in the case of miscarriage. Resting largely on the aspirations for a future generation, couples experiencing the pain of pregnancy loss question and deserve answers to the prevalence of this dark side of human biology. “Painted” as a black box by Macklon and colleagues over 20 years ago now, the factors underscoring the surprisingly high-rate pregnancy failure, especially during the earliest stages of human development, remain elusive and challenging to synthesize into a framework offering some measure of comprehension, avoidance or possible therapy [1].

What underlies this mysterious prevalence of pregnancy loss in humans has understandably drawn from the field of human genetics given historically strong associations appreciated to be inherent to genomic instability in gametes and the embryos from which they are derived. More recently, the black box may have opened ever so slightly as alternative and complementary research approaches converge in the spirit of discovery anew. Nikitina and Lebedev in recognizing the limitations and experimentally intractable nature of past efforts suggest tapping into the rich potential of stem cell biology as a pathway to solving some of the problems recognized to be at the core of miscarriage [2]. Here, our lead article, and a number of papers collated in this issue, take the notion of intercalating stem cells as a research platform into the nuances of cross talk between the endometrium and conceptus that if at all compromised due to genetic, environmental, or immunological contributions interrupt the course of pregnancy at any number of stages (see Endometrial and placental stem cells in successful and pathological pregnancies; 10.1007/s10815-023-02856).

Detailed genetic analyses are deepening the plot relative to how patterns in gene expression are collectively, for these multiple cellular players, engaged in not only establishing a pregnancy but seeing to it, or not, that placental function mediates the host conceptus relationship throughout pregnancy [3]. But as fate would have it, genetics becomes subservient to epigenetics as would well be predicted for women experiencing recurrent pregnancy loss [4]. While epigenetic regulation continues to be a target for research into the causes of miscarriage, and stem cell based models will likely serve well to uncover a more mechanistic explanation for the subtleties involved, tracing causation back to the precarious genetics of gametes and embryos is a somewhat conditioned area primed to explore with fresh eyes.

One subject line from our checkered past has revolved around the human sperm centriole. Avidor-Reiss and his colleagues have uncovered what seems a likely link between the genetic chaos seen in human embryos and the ways in which the conceptus acquires legitimacy for its ensuing mitotic divisions as assigned to either the embryo proper (ICM) or placenta [5]. With many hundreds of proteins required to construct the centriole, and yet another layer of post-translational modifications superimposed on gene products controlling microtubule assembly at the centrosome, it is no wonder that early human embryos struggle to sort their genomes on the road to successful implantation and pregnancy establishment [6]. Intricacies of this kind, at the cell and molecular regulatory levels, will hopefully someday translate into a cohesive understanding of the interactions between endometrium and conceptus. That a sophisticated communication network is key of and involves exosomes as effectors of pregnancy at the placental-uterine interface [7]. Relieving the deep psychological and medical burden imposed by miscarriage is a challenge not to be taken lightly and deserves our ongoing attention as this issue so well illustrates.

As has been tradition at JARG, midyear provides an opportunity to enhance the expertise provided by our Editorial Board members who have been sought out to complement existing topical strengths cultivated since 2009. In this vein, we first welcome Professor Lei Wang as our Associate Editor for Genetics. Joining our Editorial Board at this time are Tomer Avidor-Reiss, Anastasia Kirillova, Lacey Luense, Corrado Spadafora, Christophe Sifer, and Diane Tober. Notably, our newest board members bring a spectrum of interests enriching JARG’s coverage in areas ranging from epigenetics to anthropology. We welcome this cast of specialists who along side our existing board members serve our readership in selfless and dedicated roles that continue to drive the journal into the future of human ARTs and Reproductive Genetics.