24 - Blood Cell Formation

cell count

• RBC → 5×10¹² RBC/L of blood

  • 3×10¹³ total RBC (for 6L of blood)

  • lifespan of 120 days → 2.5×10¹¹ RBC die per day

  • rate of new RBC made → 10¹⁰ RBC/hr

• neutrophils → 1/1000 of RBC count

  • lifespan of 8 hours → massive turnover

  • rate of new neutrophils made → 10¹⁰ neutrophils/hr

sites of hematopoiesis

• mesoblastic → primitive RBC formation in yolk sac

• hepatic phase → blood cell formation in liver and spleen (first/second trimesters)

• myeloid phase → bone marrow becomes primary site of blood cell formation (mid-second trimester onward)

• young adults → all bones participate

• later adulthood

  • long bones → fatty, inactive

  • flat bones → dominant source of blood cells

monophyletic theory of hematopoiesis

all blood cells come from pluripotent hematopoietic stem cell (HSC)

• HSC can produce RBCs, platelets, granulocytes, monocytes, mast cells, lymphocytes

• HSCs rarely divide → generates one self-renewing stem cell and one progenitor cell

• HSCs usually quiescent → undergo mitosis infrequently

progenitor cells

• common progenitor cell → daughter of HSCs 

  • express genetic programs leading to committed lineages

  • contains ensemble of receptors requiring specific ligands to express

  • undergo rapid rounds of mitosis

  • not self-renewing

• committed progenitor cells → daughters of common progenitor cell

  • express genetic programs of a specific lineage

  • contain specific receptors for ligands that regulate differentiation and division

  • undergo rapid but limited number of mitotic cycles

  • not self-renewing

radiation studies

• irradiated mice lost all blood cells

• injecting marrow rescued them

• colonies formed in spleen and liver showing:

  • mixed colonies → common progenitors

  • single-lineage colonies → committed progenitors

• retroviral marking tags allowed tracing cell descendants

  • all blood lineages shared the same integration site → all from one stem cell

HSC transplantation

any HSC can give rise to all of the blood cell types

• somatic mutations in HSC can give rise to sub-population of HSCs that can cause disease

• autologous HSC transplantions using isolated normal HSCs can be used therapeutically

mitotic expansion and differentiation

each lineage survives or divides if its specific cytokine binds its receptors

• specific ensemble of plasma membrane receptors

• availability of specific ligands for receptors

• chromatin accessibility for responding to signal transduction pathways

erythropoietin (Epo)

Epo is mitogenic/differentiation factor produced in kidney and in systemic circulation 

• controlled by hypoxic response

  • low oxygen → high Epo → increase RBC

  • high oxygen → low Epo → decrease RBC

• +Epo → mitosis and cell survival

  • signal transduction leads to phosphorylation of Bad (BH3) and its inactivation

• -Epo → no mitosis but apoptosis

  • Bad (BH3) is not phosphorylated, and activates intrinsic pathway of apoptosis

erythropoiesis

driven by Epo

• committed progenitor cell

• basophilic erythroblast → heavy RNA and ribosomes (blue)

• polychromatophilic erythroblast → increasing hemoglobin (pink) and residual RNA (blue)

• orthochromatophilic erythroblast → mostly hemoglobin (pink)

• reticulocyte → no nucleus

• mature RBC → biconcave, full hemoglobin

granulopoiesis

requires lineage-specific receptors and ligands, where individual lineages have unique histological traits defining stages of differentiation

• promyelocyte → looks identical for all granulocyte lineages

  • contains azurophilic granules, not lineage specific

• myelocyte → first appearance of specific granules

  • neutrophilic / eosinophilic / basophilic myelocyte

  • based on color of granules

• metamyelocyte → indented nucleus, no more mitosis

• band cell → nucleus elongates, horseshoe shape

• mature granulocyte → segmented nucleus into lobes

thrombopoeisis

platelet formation with thrombopoietin (TPO) factor

• TPO constitutively produced in liver and kidney, in systemic circulation

• growth by endomitosis → DNA replication without cell division

• platelets formed by shearing off cytoplasmic processes extending into sinusoids

• regulated by number of platelets

  • platelets have TPO receptors that bind TPO but cannot respond to it

  • more platelets → more TPO removed from circulation, leading to less stimulation of megakaryocytes

  • less platelets → less TPO bound and free TPO increases, stimulates megakaryocytes

• negative feedback by product sequestration

bone marrow niche

• sinusoids → continuous, no open gaps

  • basement membrane is discontinuous and contains holes

  • new blood cells cross endothelium by transient transcellular pores

• chemokine abundant reticular (CAR) cells/adventitial cell → provide chemokine signals that recruit and anchor HSCs

  • express membrane-bound stem cell factor (steel factor) that binds c-Kit tyrosine kinase receptor on HSCs

  • bound state → keeps HSC quiescent

  • becomes progenitor when daughter cell detaches

    • binds free steel factor to differentiate into common progenitor cell