The term “hemogenic” describes a biological process where new blood cells are created from cells that are not blood cells. “Hemo” refers to blood, and “genic” signifies producing or generating. This concept involves the transformation of one cell type into another, giving rise to the diverse components of the blood system. Understanding this process helps explain how the body continuously replenishes its blood supply.
The Source of Blood Stem Cells
Blood cell formation begins with hemogenic endothelium. Endothelial cells are flattened cells that line the inner surface of blood vessels, forming a smooth barrier. During embryonic development, a unique subset of these endothelial cells acquires the capacity to produce blood cells.
Hemogenic endothelial cells are found in distinct anatomical locations within the developing embryo. They are present in regions like the aorta-gonad-mesonephros (AGM) region, a major site for definitive blood stem cell emergence. These cells are also identified in extraembryonic tissues such as the yolk sac and placenta, contributing to early blood cell production.
The Endothelial-to-Hematopoietic Transition
The mechanism by which hemogenic cells generate blood cells is called the Endothelial-to-Hematopoietic Transition, or EHT. This process involves a cellular transformation where an endothelial cell changes its identity to become a blood-forming cell. During EHT, the flat, adherent endothelial cell undergoes changes, rounding up and detaching from the vessel wall.
This transformed cell then “buds off” from the endothelium, becoming a free-floating hematopoietic stem or progenitor cell. The transition is a tightly regulated event, guided by specific genetic signals that orchestrate the shift in cell fate. A key regulator of this transformation is the transcription factor RUNX1.
RUNX1 acts as a molecular switch, initiating the genetic program that drives the endothelial cell towards a hematopoietic identity. Its expression is required in endothelial cells for the formation of intra-arterial clusters, which are aggregates of newly formed blood cells. This factor downregulates endothelial-specific genes while activating genes associated with hematopoietic cell development.
Significance in Embryonic Development
The Endothelial-to-Hematopoietic Transition holds importance in the developing embryo, as it represents the origin of the first definitive hematopoietic stem cells (HSCs). These HSCs are multipotent cells capable of self-renewal and differentiating into all types of mature blood cells, including red blood cells, various white blood cells, and platelets. Their emergence from hemogenic endothelium ensures the establishment of a robust and diverse blood system.
Following their generation, these HSCs migrate from their sites of origin, such as the AGM region, to colonize other developing organs. They first populate the fetal liver, where they expand in number, before migrating to the bone marrow around the time of birth. This sequential colonization establishes the foundation for the blood and immune system, which will sustain the organism throughout its lifespan.
Implications for Regenerative Medicine
Understanding the hemogenic process offers promise for regenerative medicine, particularly in developing new therapies for blood-related disorders. Scientists are working to replicate the Endothelial-to-Hematopoietic Transition in laboratory settings, often using induced pluripotent stem cells (iPSCs). These iPSCs are generated from adult somatic cells, offering a patient-specific source of cells without ethical concerns associated with embryonic stem cells.
Generating hematopoietic stem cells from iPSCs in a controlled manner could provide a vast supply of patient-matched blood cells. This innovation could revolutionize blood transfusions, offering a safer and more compatible alternative, especially for individuals with rare blood types or those requiring frequent transfusions. It also holds potential for engineering blood stem cells for bone marrow transplants, eliminating the need for a compatible donor and reducing the risk of graft-versus-host disease.
Replicating EHT in vitro could lead to new treatments for a range of severe blood disorders. Conditions such as leukemia, a cancer of blood-forming tissues, aplastic anemia, characterized by insufficient blood cell production, and various inherited immune deficiencies could be addressed by transplanting laboratory-generated, healthy hematopoietic stem cells. While challenges remain in efficiently producing fully functional, engraftable HSCs, research continues to advance our understanding and capabilities in this field.