Fetal Hemopoiesis

• Hemopoiesis is a continuous, regulated process of blood cell production that includes: cell renewal, proliferation, differentiation and maturity. The embryo requires red cells for the transport of maternal oxygen to permit its growth and development.

• During embryogenesis, hemopoiesis occur in temporally distinct sites including yolk sac, the fetal liver and the preterm bone marrow, Hence the process has been divided intothree(3) main phases; mesoblastic phase, the hepatic phase and the medullary phase.

INTRODUCTION

Erythropoiesis is established soon after implantation of the blastocyst, with primitive erythroid cells appearing in the yolk sac blood islands by day 18 of gestation. In developing embryos, blood formation occurs in aggregates of blood cells in the yolk sac called blood islands.

As development progresses,blood formation occurs in spleen, liver and occasionally thymus.

When these organs (i.e thymus,liver and spleen) resume their hemopoietic funtions,it is refered to as extramedullary hemopoiesis which may cause the organs to increase in size substantially.

During fetal development,liver functions as the main hemopoietic organ since the bones and bone marrow are yet to develop and as such the liver is enlarged during development.

MESOBLASTIC PHASEo Hematopoiesis generally is considered to begin on

the 19th day of embryologic development, after fertilization.

o Progenitor cells of mesenchymal origin migrate from the aorta-gonad-mesonephros region of the developing aorta-splanchnopleura to the yolk sac.

o The cells arising from the aorta-gonad-mesonephros region give rise to hematopoietic stem cells [HSC’s], but not to primitive erythroblasts found in the yolk sac which arising from mesodermal cells, initially line the cavity of the yolk sac.

These primitive cells migrate from periphery into the central cavity of the yolk sac where they develop into primitive erythroblasts.

The remaining cells surrounding the cavity of the yolk sac are called ANGIOBLASTS and form the future blood vessels.

The yolk sac phase of hemopoiesis is characterised by the development of primitive erythroblasts that produce measurable amounts of hemoglobin.

This phase of hemopoiesis occurs intravascularly, or within a developing blood vessel(that is within the vascular network rather than in the extracellular space) and does not contribute significantly to definitive hemopoiesis.Yolk sac erythroblasts remain nucleated as they circulate. They are characterised by more rapid maturation,increased sensitivity to erythropoietin and a shortened life span compared to fetal and adult erythroblasts. They are extremely large cells (megaloblasts).

The yolk sac erythroblasts have increased sensitivity to erythropoietin

HEPATIC PHASE

• The liver serves as a primary source of red cells from 9th to the 24th weeks of gestation and is characterised by recognizable clusters of developing erythroblasts,granulocytes and monocytes.

• The developing erythroblast in this phase signal the beginning of definitive hemopoiesis with a decline in primitive hemopoiesis of the yolk sac.

• In addition,lymphoid cells begin to appear, in this phase,hemopoiesis occurs extravascularly.The hemoglobins present in this phase include; HbF,HbA,HbA2.

• The liver remains the primary site of erythropoietin transcription throughout life.

The fetal liver contains abundant hematopoietic progenitor cells including CFU-GEMM(Colony forming units –granulocyte-erythroid –monocytes-macrophages and CFU- GM(Colony forming unit granulocyte-monocyte).

Along with the development of the hemtopoietic system, the liver acquires the characteristics of the metabolic organ(that is,it shows an increase in size).

Furthermore, Oncostatin M(OSM),an interleukin -6- family cytokine,in combination with glucocorticoids induced maturation of hepatocytes.

NB: Oncostatin M is expressed in the liver and it’s receptor is expressed predominantly in hepatocytes. This largely accounts for a transient expansion of the fetal liver during this stage.

o On analysis, fetal liver revealed a significant reduction in hemopoietic stem cell pool, suggesting the reduction in cellularity observed postnatally and is due to insufficient expansion during fetal development.

o Since Beta-catenin correlated with cell proliferation during prenatal liver development and regeneration,analysis carried out showed that total beta-catenin protein levels were low at birth(postnatal days 0-5),but were induced at postnatal day 5 and remained elevated until postnatal day 20 and returning to near adult levels(old livers) during postnatal days 25-30.

In addition,studies have shown that the polyubiquitin(Ubc)gene is required for fetal liver development and it was highly expressed in hematopoietic cells,hence a transfer of the hematopoietic process to the bone marrow may lead to a decrease or slowing down of the fetal liver development.

Hemopoietic cells of the fetal liver exist in a specific microenvironment that controls their proliferation and differentiation.

This microenvironment is created by different cell populations, including epitheliocytes, macrophages various stromal elements(fibroblasts, myofibroblasts, vascular smooth muscle and endothelial cells, mesenchymal stromal cells).

Hemopoietic function of the organ reaches its peak during the first 2-4 postnatal days.

MEDULLARY (MYELOID) PHASEo It begins in 5th month of development and occurs in medulla

of bone marrow.

o Mesenchymal cells migrate into bone and differentiate into skeletal and hemopoietic cells.

o Detectable levels of substances such as; EPO,fetal Hb,adult Hb, etc. occurs in this phase.

o Tissues where lymphoid development occurs are classified into primary and secondary lymphoid tissues. The primary includes the bone marrow,thymus and is where T&B cells are derived.

The secondary includes spleen, lymph nodes,gut association lymphoid tissue and is where lymphoid cells become competent.

There are two types of marrow which are,the red bone marrow and the yellow bone marrow .

The yellow marrow is hemopoietically inactive and composed of adipocytes while the red are found in the sternum,skull,scapulae,ribs,vertebrae,etc

In newborns, all marrow is red but most later becomes yellow.

REGULATION OF HEMOPOIESIS

o It is regulated by various cytokines. The combination of various cytokines stimulate the proliferation and/or differentiation of various hemopoietic cell types. Bone marrow stromal cells are the major source of hemopoietic cytokines in the non-infectious state. In the presence of infection, cytokines produced by activated macrophages induce hemopoietic activity. Some hemopoietic growth factors such as the Granulocyte –Macrophage colony stimulating factor are given to stimulate white blood cell formation in cancer patients receiving chemotherapy which kills their red bone marrow cells as well as cancer cells.

Clinical Correlates

Knowledge of the unique characteristics of fetal hematopoiesis and the changes that occur at and around birth is a necessary backdrop for understanding the differences between neonatal and adult blood.

Erythropoietin (EPO ) has a central role in regulating the rate of proliferation and differentiation of erythroid precursors, as it is the most important cytokine regulator of mammalian erythropoiesis. Targeted disruption of EPO or its receptor leads to almost complete blockage of fetal liver erythropoiesis, resulting in fetal death.

CLINICAL CORRELATES

Trisomy 21 is associated with an increased frequency of pediatric acute leukemia,especially megakaryoblastic leukemia and acute lymphoblastic anaemia(ALL)

Trisomy 21 induces perturbation of hematopoiesis in the human fetal liver. They show 2 types of abnormalities:

1.A bias in hematopoietic stem cells towards the erythrocyte-megakaryocyte lineages with an increase in megakaryocyte-erythroid progenitors.

2.Impaired B cell differentiation with a marked decrease in B cell progenitors.This indicate that trisomy 21 induces multiple distinct defects in fetal hematopoiesis,which favour the emergence of transient myeloproliferative disorder and megakaryoblastis as well as B cell leukemia.

Thank you…

BY GROUP 2 MEMBERS:Mayowa Oleseni, Elizabeth Peters,

Deborah Ndiomu, Blessing Ibe,

Oluwanifemi Babade, Ibukunoluw Olowoyo,

Adewale Towobola, Olayinka Gbadebo,

Mercy Omosigho, Mogbonjubola Ilesanmi,

Sandra Awoniyi.