Normal Hematopoesise

Constituents of Blood and Bone marrow and regulation of

hematopoiesis

Dr Deepti Joshi

AIIMS Bhopal

Cells of Blood

Peripheral smear

Blood cells are derived from bone-marrow

Common ancestor of all blood cells

All blood cells are progeny of a single cell type (Hematopoeitic Stem cell or HSC)

Processes involved in production of various types of blood cells is Hematopoeisis

Hematopoeisis included self-renewal of stem cells,commitment to specific lineages and maturation of lineage committed progenitors to functional blood cells.

Sequence of events

Stem cells

Progenitor cells (recognized by culture techniques)

Recognizable proliferating marrow precursors

Mature cells

Progenitor Cells of erythroid series: BFU-E

Earliest defined erythroid progenitor. It is called a burst because it of its ability to create a "burst" on

semisolid media, i.e. a colony consisting of several hundred to thousand cells in 10 -14 days.

Requires IL-3 Granulocyte-macrophage colony stimulating factor Erythropoietin

For proliferation, prevention of apoptosis, & differentiation to morphologically recognizable erythroid precursors

10-20 % are in cycle at a time Found in significant nos. in peripheral blood

CFU-E

BFU-E differentiates into colony forming uniterythroid.

Identified in vitro by smaller colonies (50200 cells) that grow in 3 to 5 days.

However, EpoR density & Epo dependency gradually as progenitor cells mature, culminating at the level of the CFU-E.

BFU-E and CFU-E cannot be identified by microscopy

Changes in properties during differentiation of erythroid progenitors

Subdivisions of Hematopoeisis

Lymphopoeisis

Myelopoeisis

Granulopoeisis

Monocytopoeisis

Erythropoeisis

Megakaryopoeisis

HSCs reside in bonemarrow but under stress can get tranferred to other organs like liver and spleen (Extramedullary hematopoeisis)

HSC can give rise to non-hematopoeitic cells

Turnover and replenishment of the hematopoeitic system continues through out the life

Regulation of hematopoeisis is a complex process.

Embryonic Yolk sac

5th gestational week Rudimentary liver

7th week onward Liver is the dominant site until the 30th gestational week

6th month onward Cavities of long bones

At birth All bone cavities are actively engaged in erythroid production, the hepatic (fetal) phase of erythropoiesis comes to an end

Sites of hematopoeisis

Some RBC production can be found in thymus, spleen, or lymph nodes,

these sites are never dominant. Foci of hematopoietic activity detected within

the embryo around the developing aorta (in the paraaortic-splanchnopleura [P-

Sp] & the aorta/gonad/mesonephros [AGM] area.

Structure of hematopoietic organ

Anatomic structure (3 D organization of different tissue types and their component cells) Stroma Hematopoeitic progenitor cells and their progeny (Erythroid, Myeloid, and megakaryocyte series)

Bone-marrow anatomy

Largely anatomic features of hematopoietic organs are unknown

Functions of the cells of venous sinuses within the marrow understood

Venous structure is a complex maze of sinuses that drain into central veins

Hematopoeitic progenitors differentiate outside these sinuses

Formed by a continuous layer of endothelial cells which on extra-luminal side are covered by fenestrated adventitial reticular cells

EC provide selective exit of mature blood cells from the marrow into the blood stream.

Hematopoeitic stem cell niche

Bone-marrow stromal niche supports HSC activity

Two types of HSC niche: Osteoblastic niche and vascular niche

Marrow stromal niche maintains the quiescence of the HSC and releases committed progenitor cells while vascular niche harbours the progenitor cells before releasing them into circulation

Stroma

Important for Stem cell renewal Homing of HSC to the hematopoeitic organs Egress of mature hematopoeitic cells from bone

marrow into blood various cells as well as the extracellular

macromolecules that occupy the hematopoeitic tissue along with the hematopoeitic cells

Includes myofibroblasts,adipocytes,macrophages,plasma cells,lymphocytes,endothelial cells,stem cells

It constitutes the microenvironment in which the cells grow and differentiate

Morphologically identifiable erythroid series

Morphologically identifiable Myeloid series

Normal granulocyte precursors in the bone marrow

Metamyelocyte & Band form

Megakaryoblasts

Megakaryoblasts are the precursors of the megakarycytes.

They may show cytoplasmic blebbing.

Megakaryocyte

Regulation of hematopoeisis

Local environmental control.

Role of haemopoeitic growth factors (Humoral regulation)

Apoptosis

Complex interaction between stromal cells,growth factors and hematopoeitic cells

Adhesion molecules

Transcription factors

Hematopoeitic growth factors

GM-CSF

M-CSF

Erytropoeitin

Thrombopoeitin

Cytokines

C-kit 3 and FLT-3 (act on early progenitors)

Transcriptional factors

GATA1 and PU.1 (Myeloid commitment)

GATA 1and fog1 (erythroid)

PU.1 (Common lymphoid )

Erythropoeisis

Process of development of red cells from precursor cells is known as erythropoeisis.

Collectively, the progenitor & adult RBCs are termed the erythron to reinforce the idea that they function as an organ.

Divided into two phases-EPO dependent and EPO independent

Thank You.