Lecture 3: Hematopoiesis

All mature blood cells including RBC + WBCs arise from what?

HSC - Hematopoietic stem cells

• the cell type from which all lineages of blood cells arise

Define hematopoiesis

The processes of formation and differentiation of blood cells

*****What is the hotspot regions of Hematopoiesis in Adults?

Bone marrow (yellow marrow)

• pelvis, sternum, vertebrae, and proximal ends of our limbs

****Stem cells are defined by what 2 capacities?

1. Ability to regenerate or “self renew”

2. Ability to Differentiate into diverse cell type

*****How are EMBRYONIC SCs different than ADULT SCs?

Embryonic = have the capacity to generate almost every specialized cell type in an organism: they are considered pluripotent

Adult = Have the capacity to give rise to the diverse cells types that specify a particular tissue: they are considered Multipotent

• many adult organs harbor stem cells that five rise to cells for that specific tissue (tissue specific stem cells)

****What was the first tissue specific stem cell identified?

HSC (hematopoietic SCs)

• Source of RBC and WBC

****Where do HSCs originate and where do they primarily reside?

• Where are a small portion of HSCs found?

Originate in fetal tissues and reside primarily in the bone marrow of adult

vertebrate.

• Small number may be found in adult spleen and liver.

****Are HSCs RARE or COMMON cells?

Rare

• less than 50000 in the bone marrow.

***HSC numbers are strictly controlled by what? (3 events)

a balance of cell division, death, and differentiation

****What are HSCs like under steady state or homeostatic conditions (NO infection)

Most HSC are resting

• Only a small number divide, generating daughter cells

****What are the 2 possible fates of HSC DAUGHTER CELLS

• Some daughter cells retain the self-renewal characteristics of the mother cell = replenish the source

• Some daughter cells differentiate

****What do HSCs Differentiate into?

progenitor cells

• Myeloid + Lymphoid progenitors

***What are PROGENITOR CELLS? how do they differ from HSCs?

Limited self-renewal capacity

Become progressively more committed to a particular blood cell lineage

****Where is the ONLY LOCATION that progenitor cells are found in the hematopoiesis process?

BONE MARROW

• progenitors are not allowed outside/ not found outside the bone marrow (generally)

*****EXCEPTIONS: What is the ONLY cell that can EXIT the Bone marrow still as a progenitor

T- CELLS

• Go to the thymus to continue maturation

***What are the processes that occur in the BONE MARROW?

Differentiation of HSCs into PROGENITOR CELLS

• Generally all cells undergo a progenitor precursor stage in the bone marrow

*****EXCEPTIONS: What are 2 cells that are can skip the Progenitor stage

1. MAST CELLS

2. ILC (innate lymphoid cells)

*How does the number of HSCs change as one ages? Why?

Number of HSCs decreases (there are limits to self-renewal)

*****EXCEPTIONS: What is the ONLY cell that can be derived from both myeloid + lymphoid cells?

DENDRITIC CELLS

• but in this case we will mostly be referring to myeloid derived dendritic cells

****List the MYELOID vs. LYMPHOID cells

Myeloid

• dendritic

• Monocytes => Macrophages

• Neutrophil

• Eosinophil

• Basophils

• Platelets

• Erythrocytes

• Mast Cells

Lymphoid

• Dendritic

• B cells

• T cells

• ILC (innate Lymphoid cells)

Key concepts: All RBCs and WBCs develop from _______ ________during a highly regulated process called _______

All RBCs and WBCs develop from multipotent HSCs during a highly regulated process called

hematopoiesis.

Key concepts: Hematopoiesis occurs in the adult _____ ______ __________ that supports both the ______ and ________ of the HSC into multiple cell types

Hematopoiesis occurs in the adult vertebrate Bone Marrow (a primary lymphoid organ) that supports both the self-renewal and differentiation of the HSC into multiple cell types

*****What are the specific stages that a HSC undergoes after it is induced to differentiate and before dividing into myeloid/lymphoid progenitors?

• Hint: 3 different stages of differentiation

LT hsc

ST hsc

MPP

*****What is a LT-HSC, ST-HSC and MPP?

• differences between them

As an HSC continues to differentiate it LOSES its ability to SELF RENEW as it progresses from LT-HSC to MPP

• LT-HSC = LONG TERM HSC are the most quiescent (inactive) and retain pluripotency throughout the life of an organism maintain the stem cell pool

• ST-HSC = mainly quiescent but divide more frequently and have limited self renewal capacity

• MPP = Multipotent progenitors have LOST the capacity for self-renewal, but can proliferate rapidly and give rise (i.e., differentiate) along multiple hematopoietic lineages

****What are the 4 hematopoietic lineages that MPPs can give rise to?

Lymphoid, myeloid(granulocytes, monocytes, macrophages, and some DC ), erythroid, and megakaryocytic.

*****What are the the 2 lineage commitment choices an MPP cell can make?

• aka what is the next step in differentiation after MPP?

• Myeloid Progenitor

• Lymphoid Progenitor

***What cells do MYELOID vs. LYMPHOD+ID progenitors give rise to?

• Myeloid Progenitor: RBCs, platelets, and myeloid cells (e.g., granulocytes, monocytes, macrophages, and some DC populations).

• Lymphoid Progenitor: B and T lymphocytes, innate lymphoid cells (ILCs), as well as specific DC populations.

  • ILCs have features of both innate and adaptive cell

*****EXCEPTIONS: Precursors of of RBCs and platelets can also arise directly from the earliest HSCs

****What are the next steps of differentiation from a Myeloid or Lymphoid progenitor?

Myeloid

• DC

• Granulocyte-monocyte Progenitors

• Erythroid Progenitors

Lymphoid

• DC

• T cell progenitors

• B cell progenitors

Key concepts: The HSC is a ___ (rare/common) cell type that is ______

and _______, which also has the capacity to ________ or rapidly replace blood cells.

The HSC is a rare cell type that is self-renewing and multipotent, which also has the capacity to differentiate and rapidly replace blood cells.

Key concepts: HSCs include multiple subpopulations that vary in their ______ and capacity to _______

HSCs include multiple subpopulations that vary in their quiescence and capacity to self-renew

• LT HSC

• ST HSC

Key concept: ______ are the most quiescent and long-lived. They give rise to ______ which can develop into more proliferative ______, which give rise to _____or_____cell types

• outlines the specific stages of HSC differentiation

Long-term HSCs are the most quiescent and long-lived. They give rise to short-term HSCs, which can develop into more proliferative MPPs, which give rise to lymphoid and myeloid cell types

Key concept: HSCs that are induced to differentiate make one of two broad lineage choices:

1. They can give rise to CMPs (common Myeloid progenitors) that develop into myeloid cell types.

2. They can give rise to CLPs (common Lymphoid progenitors) that develop into lymphoid cell types

*****As progenitors differentiate, they progressively LOSE WHAT 2 ABILITIES?

1. Self-renew

1. Ability to give rise to other cell lineages.

Major Myeloid and Lymphoid cell types, their life spans, and relative amounts in our blood.

• ARRANGED based on AMOUNTS in blood

****What is the TRADITIONAL method used to Distinguishing Blood Cells under the Microscope

H + E stain = a pH sensitive stain

• Hematoxylin Eosin

********What part of the cell does Hematoxylin vs. Eosin stain? What is their respective COLOUR? Which is an acidic dye and which is a basic dye?

Hematoxylin = basic dye

• binds basophilic (neg - charged) nucleic acids

• BLUE.

Eosin = The acidic dye

• binds eosinophilic proteins (pos + charged) in the granules and the cytoplasm

• PINK