Revisiting Hematopoietic Hierarchy: Emerging Insights into Megakaryocyte-Biased Differentiation Pathways of Hematopoietic Stem Cells

Hematopoietic stem cells (HSCs) represent the most primitive cell population endowed with the ability for self-renewal and differentiation. They possess the capacity to differentiate into all types of blood cells, each serving unique functions. Traditional theories have established a clear hierarchical relationship between HSCs, their progenitors, and mature blood cells. The identification of distinct cell populations within the hematopoietic system forms the foundation of the hematopoietic differentiation model. However, recent research has led to a constant evolution of our understanding of the hierarchical structure of hematopoietic differentiation, particularly in the context of megakaryocyte differentiation pathways. Megakaryocytes are essential for platelet production, a critical process in hemostasis and thrombosis. Understanding the mechanisms underlying megakaryocyte-biased HSCs differentiation holds significance for both basic research and clinical applications. In this review, we consolidate the latest research progress concerning the evidence supporting these nonclassical pathways of megakaryocytic differentiation. Furthermore, we delve into the alterations observed in these pathways under conditions of steady state, transplantation, stress, and aging.