Under the Microscope - Hematopoietic Stem Cells (April 2022)

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Under the Microscope: Hematopoietic Stem Cells

By:
Miriam Lopez-Parra, MD
Hematologist - University Hospital of Salamanca
Salamanca, Spain

Sandra Muntion, PhD
Cell Therapy Lab, IBSAL - University Hospital of Salamanca
Salamanca, Spain

Declarations of interest: none.

Confocal microscopy image of Hematopoietic Stem Cells after immunomagnetic sorting. CD34⁺ cells were labeled with anti-CD45 antibody (in green) and nuclei were stained with DAPI (in blue).

What? Hematopoietic Stem Cells (HSC) are a rare population of cells, representing less than 0.01% of all cells in the bone marrow. The two defining features of HSC are^1-2:

Self-renewal: the ability to give rise to identical daughter HSCs without differentiation
Multi-potency: the ability to differentiate into all functional blood cell types.

These two abilities make HSC an attractive source of stem cell-based therapies. However, HSC and committed progenitor cells are morphologically indistinguishable, and require immunophenotyping for identification of HSC. The first surface marker used to enrich human HSC was CD34, which is a ligand for L-selectin. Currently, CD34 is the main marker used to determine whether a graft contains sufficient HSCs for clinical engraftment after allogeneic and autologous hematopoietic transplantation.

Why? HSC can reconstitute long term hematopoiesis and immune system. HSC transplantation can be a life-saving procedure in the treatment of a broad spectrum of disorders, including hematologic, immune and genetic diseases³.

When? The development of atomic weaponry in the first half of the 20^th century led to the interest and in understanding how ionizing radiation damages normal tissue and whether the effects of a lethal dose could be abrogated by a medically applicable intervention. HSC research took hold in the 1950s with the demonstration that intravenously injected bone marrow cells can rescue irradiated mice from lethality by reestablishing blood cell production. Till and McCulloch⁴, 1961 laid out the first experimental demonstration of the self-renewing unit in the hematopoietic system. In 1969, they proposed that these self-renewing units are a primitive cell source capable of giving rise to multiple lineages that together can regenerate the whole hematopoietic system. They hypothesized these units to be stem cells. This fact marked the beginning for hematopoietic stem cell transplantation. Since 1990, the number of autologous and allogeneic hematopoietic stem cell transplantation has continued to increase⁵.

Where? The bone marrow is where HSC are housed, receiving physiological inputs to modify their activity in response to changing physiological demands³. The factors that regulate the production and behavior of HSC in this microenvironment are not completely understood but include a complex stromal cell network that provides a framework where developing cells are bound and essential hematopoietic growth factors and cytokines are produced. Cell types involved in this microenvironment include: osteolineage committed cells, fibroblastic-like cells, endothelial cells, macrophages and adipocytes⁶. The most important growth factors in HSC homeostasis include Stem Cell Factor (SCF), FLT3 ligand, Wnt, Jagged, Bone Morphogenic Protein (BMP) and angiopoietin-like growth factors. Negative regulators consist of TGF beta and osteopontin^7-9. HSC can also be found in the neonatal blood obtained from the umbilical cord or the placenta immediately after delivery.

How? The most common HSC sources for transplantation are bone marrow and mobilized peripheral blood stem cells, but umbilical cord blood can be used as a graft source as well.

Did you know that… mature blood cells derived from HSC are produced at a rate of more than one million cells per second in adults?

References

Seita J, Weissman Il. Hematopoietic stem cell: self-renewal versus differentiation. Wiley Interdiscip Rev Syst Biol Med. 2010;2:640-53
Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 2006; 6:93
Copelan, E. A. Hematopoietic stem-cell transplantation. New Engl. J. Med.354, 1813–1826 (2006).
Till Je, McCulloch Ea. A Direct Measurement of the Radiation Sensitivity of Normal Mouse Bone Marrow Cells. Radiation Res 1961; 14: 213-222
Passweg J, Baldomero H, Chabannon C. Hematopoietic cell transplantation and cellular therapy survey of the EBMT: monitoring of activities and trends over 30 years. Bone Marrow Transplantation 2021; 56, 1651-1664
Ding L, Saunders TL, Enikolopov G. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 2012; 481:457
Ogawa M. Differentiation and proliferation of hematopoietic stem cells. Blood. 1993;81 (11): 2844-2853
Han W, YuY, Liu XY. Local signals in stem cell-based bone marrow regeneration. Cell Res. 2006;16:189-95
Yang Liu, Qi Chen, Hyun-Woo Jeong. A specialized bone marrow microenvironment for fetal haematopoiesis. Nat Commun (2022)13:1327