Megakaryocytopoiesis is the process by which megakaryocytes, the precursors to platelets, are produced during adult hematopoiesis. This process involves complex interactions between growth factors, cytokines, transcription factors, and signaling pathways that regulate the differentiation and maturation of megakaryocytes. Once mature, megakaryocytes undergo cytoplasmic fragmentation, producing thousands of platelets that are released into circulation. For the purpose of creating novel treatments for blood and vascular system illnesses, it is essential to comprehend the processes behind megakaryocytopoiesis and platelet production. Ontogenetic variations may last in children up to the age of 2-4 years and seem to be more evident in fetal liver and embryonic stem cell progenitors. These developmental differences have clinical significance because CD34+ hematopoietic stem cells derived from cord blood are linked to a delayed platelet recovery following stem cell transplants. These findings are further supported by a poorly understood platelet hypo-responsive phenotype that may be predisposed to hemostatic incompetence. Nothing is known about developmental changes that offer genetic justifications for functionally diverse responses or that offer particular biomarkers for monitoring newborn megakaryocytopoiesis. Protease activated receptor-1 (PAR1) mediates phosphatidylserine exposure in thrombin-activated human platelets, with minimal to no involvement from PAR4. Hence, agonist-effector responses and comparisons of individual responses between cohorts may both be used to quantify this diversity in phenotypic responses. In fact, it is likely that the variation in platelet responses may be attributed to a quantitative feature controlled by several genes functionally incorporated into interaction networks.
In a recent study published in the peer-reviewed Journal of Thrombosis and Haemostasis, Dr. Zhaoyan Liu, Cecilia Avila, Ms. Lisa Malone, Dmitri Gnatenko, Dr. Jawaad Sheriff, Wei Zhu, and led by Professor Wadie Bahou from Stony Brook University conducted detailed functional and transcriptome profiling in adult and neonatal cord blood platelets. Their research sought to provide a thorough framework for comprehending the genetic networks and processes that control platelet reactivity during maturation.
The research team revealed the functional and genetic differences between cord blood and adult platelets, which reflect ontogenetically separate phases of platelet development. Their multi-parameter quantitative studies were created with the express purpose of analyzing the linear and synergistic relationships controlling activation-dependent signaling responses. Agonist-receptor interaction associated with phosphatidylserine exposure and -granule release was still possible in adult and cord blood platelets, however cord blood responses were muted for all agonists tested. These findings differed from cross-agonist activation, in which adult platelets showed robust correlations between agonists coupled to the same effector, likely reflecting pathway maturation. These relationships were not present in cord blood platelets, suggesting that synergistic signaling networks in cord blood platelets developed later than those in adult platelets. In fact, a specific maturation deficit in the protein secretory network was discovered by their genetic research. The authors found that cord blood platelets are richer in ribosomes, offering a further mechanism for preventing platelet degradation and supporting earlier findings that showed a prolonged neonatal platelet longevity in small animal studies. Their observations indicate that young ontogenetic age and ribosome enrichment may together extend platelet longevity in the early post-natal period, albeit the exact mechanism(s) behind this impact is/are unknown.
The authors found that the gene DEFA3 (HNP-3) is extremely prevalent in cord blood platelets but has only low expression in adults. In developing neonatal megakaryocytes (and cord blood platelets), DEFA3 mRNA is an inducible and abundant transcript that exhibits analogous protein expression patterns, which are statistically more pronounced than those seen during adult-derived megakaryocytopoiesis. Peak neonatal megakaryocytes DEFA3 level is higher than that of leukocytes, and although not statistically substantially higher, cord blood platelets exhibit around 2-fold more HNP-3 protein than adult platelets. These findings suggest that neonatal megakaryocytes and cord blood platelets have a microbicidal role during gestation. While mature-dependent expression of HBG1 and DEFA3 (including DEFA3 antigen) in developing neonatal megakaryocytes is most consistent with neonatal megakaryocytes origin of these transcripts, platelets may sequester RNA from external sources. It is yet unknown what, if any, importance the partitioning and accumulation of specific “erythroid” cargo in developing neonatal megakaryocytes (both adult- and cord blood -derived) has to do with.
In summary, the importance of neonatal thrombopoiesis markers lies in their ability to diagnose platelet disorders, monitor platelet function, identify risk factors for bleeding or thrombosis, and facilitate the development of new therapies. Professor Wadie Bahou and colleagues identified a stage of neonatal thrombopoiesis that is ontogenetically distinct and offer the first feasibility studies for monitoring aberrant fetal-to-adult megakaryocytopoiesis in vivo. Researchers will continue to investigate the complex mechanisms that regulate platelet production and function in newborn infants.
Liu Z, Avila C, Malone LE, Gnatenko DV, Sheriff J, Zhu W, Bahou WF. Age‐restricted functional and developmental differences of neonatal platelets. Journal of Thrombosis and Haemostasis. 2022 ;20(11):2632-45.