Erythrocytes in the fetus have different origin from those after birth

Hematopoietic stem cells (HSC) continue to self-renew and differentiate into mature blood cell lineages throughout their lifetime. Over time, hematopoietic stem cells generate erythrocyte precursors that produce red blood cells in a step-wise process called erythropoiesis. Hematopoietic stem cells first differentiate into megakaryocyte/erythrocyte progenitors, burst forming unit erythroid cells, and finally into colony forming unit (CFU)-erythroid cells. These continue to differentiate progressively until they form red blood cells.

Three overlapping processes characterize the initiation and development of a mouse blood cell production (hematopoiesis). First, blood cells of the erythroid lineage appear in the yolk sac at embryonic day 7.5. Erythromyeloid progenitors appear at around embryonic day 8.5 and hematopoietic stem cells after embryonic day 8.5. Hematopoietic stem cells enter circulation and colonize the fetal liver, where they progressively differentiate into blood lineages.

Hematopoiesis in the yolk sac gives rise to megakaryocytes, erythrocytes, and a fraction of myeloid cells. Put together, these cells maintain tissue oxygenation and hemostasis. Initially, scientists believed hematopoietic stem cells replaced yolk sac-derived cells after hematopoietic stem cells colonized the fetal liver on embryonic day 10.5. However, recent research has uncovered that the yolk sac can supply tissue-resident cells (macrophages) that can stay in tissues throughout life, and mast cells that are preserved till birth.

Erythromyeloid and hematopoietic stem cell precursors share transcriptional regulators and surface markers and are consequently indistinguishable. Therefore, it can be challenging to define their role in erythropoiesis. Moreover, understanding the process of embryonic and fetal erythropoiesis may further bring new concepts into innovative treatments of many diseases. In this regard, Institut Pasteur researchers in France, Dr. Francisca Soares-da-Silva, Dr. Laina Freyer, Dr. Ramy Elsaid, Odile Burlen-Defranoux, Dr. Lorea Iturri, Odile Sismeiro, Dr. Perpétua Pinto-do-Ó, Dr. Elisa Gomez-Perdiguero, and led by Professor Ana Cumano reported plenty of Kit⁺CD45⁻Ter119⁻ erythroid precursors unique to fetal liver. These progenitors comprised more than 70% of embryonic day 14.5 Ter119⁻CD45⁻ cells, which made up more than 10% of total fetal liver cells. Kit⁺Ter119⁻CD45⁻ cells originate from yolk sac erythromyeloid progenitors, survive the gestation period, and are the main contributors to the red blood cells compartment.  The original research article is now published in the Journal of Experimental Medicine.

The research team used two lineage-tracing mouse models for their study. One main objective for the authors was to show that, contrary to the long-standing assumption, hematopoietic stem cells only contribute to erythrocyte production to a smaller extent up until birth. The researchers reported Kit⁺CD45⁻Ter119⁻ hematopoietic cells unique to the fetal liver from embryonic day 11.5 until birth. They observed that these cells yielded between 50 and 70% more erythroid colonies than bone marrow megakaryocyte/erythrocyte progenitors. These cells required c-Myb expression and originated from the yolk sac erythromyeloid progenitors. Majorly, CD45⁻Kit⁺ cells expressed CD24 and CD71, erythrocyte progenitors’ unique transferrin receptor. The authors reported that these cells persisted throughout fetal life.

By tracing the progeny of hematopoietic stem cells in Cdh5^CreERT2 Rosa26^YFP where fluorescence is induced at embryonic day 10.5, the authors discovered that hematopoietic stem cells didn’t considerably contribute to embryonic erythropoiesis. Yolk sac erythromyeloid precursors give rise to the embryonic red blood cell compartment and also to tissue resident macrophages. After intra-embryonic injections, the researchers reported proliferative erythroid precursors rapidly differentiating and persisting in contributing to the embryonic erythroid compartment. In addition, yolk sac erythrocyte progenitors required 10X lower erythropoietin concentrations than hematopoietic-derived progenitors. This could sufficiently explain the selective advantage of yolk sac erythropoiesis over hematopoietic stem cells in red blood cell production. Professor Ana Cumano and her research team findings suggest that embryonic erythropoiesis originates from the yolk sac in humans as well, providing a great advance in the understanding of hematopoiesis in the yolk sac and will go a long way in providing an understanding of fetal hematopoiesis and the pathogenesis of fetal and neonatal erythrocyte abnormalities.