Hematopoietic Stem Cells
1. Introduction
Hematopoietic stem cells (HSCs) are named "heme" for blood. These stem cells produce our red blood cells (erythrocytes), our white blood cells (leukocytes), and other immune cells, including natural killer cells, neutrophils, basophils, eosinophils, platelets, dendritic cells, lymphocytes, and monocytes that transform into macrophages. Hematopoietic stem cells are found in the bone marrow, umbilical cord and in our blood circulation. Hematopoietic stem cells are mobilized in the bone marrow niche when there is an illness or injury. They are also mobilized in a circadian 24-hour rhythm each day to flow through the blood circulation, checking for cell damage. If there is bleeding, the HSCs signal to the bone marrow for a rapid expansion of progenitor cells to repair the cells, replace the blood, and send in immune cells to fight any infections.
Giudice A, Caraglia M, Marra M, Montella M, Maurea N, Abbruzzese A, Arra C. Circadian rhythms, adrenergic hormones and trafficking of hematopoietic stem cells. Expert Opin Ther Targets 2010;14(5):567-75. on-line reference
b.Obesity and the Bone Marrow Niche
In the bone marrow microenvironment that serves as a niche to mesenchymal and hematopoietic stem cells, conditions that disturb the bone marrow structure also disrupt the numbers and lineage-fates of these key stem cells and their progenitors. Obesity increases the size and number of adipocytes (fat tissue) encroaching into the bone marrow space, that eventually disturb HSC interactions with neighboring cells. In addition, B-cell leukocytes require signals from the mesenchymal stem cells and osteoblasts (bone forming cells) for their differentiation. As more fat cells interfere with the niche communication, they also disrupt the production of leukocytes. When old mice were fed a high fat diet, B-cell proportions were reduced by 10%. After 6 weeks, the B-cell levels were diminished by 25%. The growth factors that support B-cell differentiation (interleukin-7) also dropped over the weeks, so less B-cells could be produced. This article shows how susceptible the bone marrow is to a poor diet and how much disruptions can interfere with the blood-bone-immunity interrelationship.
Adler BJ, Kaushansky K, Rubin CT. Obesity-driven disruption of haematopoiesis and the bone marrow niche. Nat Rev Endocrinol 2014;10(12):737-48. on-line reference
Adler BJ, Green DE, Pagnotti GM, Chan ME, Rubin CT. High fat diet rapidly suppresses B lymphopoiesis by disrupting the supportive capacity of the bone marrow niche. PLoS One 2014;9(3):e90639. on-line reference
c. Hematopoietic Self-Renewal
Hematopoietic stem cell self-renewal is key to their reconstituting ability. The authors show that interleukin-10 (IL-10) an immune modulating cytokine, plays a role in regulating HSC self-renewal. This process helps these stem cells contribute cell repair and regeneration throughout a person's life.
Kang YJ, Yang SJ, Park G, Cho B, Min CK, Kim TY, Lee JS, Oh IH. A novel function of interleukin-10 promoting self-renewal of hematopoietic stem cells. Stem Cells 2007;25(7):1814-22. on-line reference
d. Homing
Hematopoietic stem cells are triggered by a complement cascade to leave the bone marrow and circulate through the blood. At the bone marrow-blood entrance, granulocytes and monocytes release enzymes that digest the endothelial barrier, allowing the HSCs to follow behind them. Homing factors that include stromal-derived factor 1, and extracellular uridine 5-triphosphate (UTP) and ATP (energy from damaged mitochondria), provide guidance to the stem cells to "home" to the area of tissue damage and begin their repair work. In clinical conditions, anti-microbial peptides, prostaglandin E2 and/or hyaluronic acid could be used in cultures to increase homing in hematopoietic stem cell transplants.
Ratajczak MZ. A novel view of the adult bone marrow ste cell hierarchy and stem cell trafficking. Leukemia 2014, Dec 9 [Epub ahead of print]. on-line reference
2. The Bone and the Immune System
The bone and immune cells have overlapping regulatory mechanisms. For example, the osteoclasts (the bone-resorbing cells) are derived from the myeloid precursor cells that produce macrophages and dendritic cells. However, osteoblasts (the bone forming cells) regulate the hematopoietic stem cell niches and therefore all the blood and immune cells that are produced. Immune cell cytokines and growth factors regulate both the osteoblasts and osteoclasts. This knowledge has led to the interdisciplinary osteoimmunology field and further research on diseases that affect both osteoporosis and immune dysfunction.
Mori G, D'Amelio P, Faccio R, Brunetti G. The Interplay between the bone and the immune system. Clin Deve Immunol 2013;2013:720504. on-line reference
3. Exercise and Stem cells
The authors suggest that exercise increases hematopoietic stem cell quantity, primarily mediated by adaptations in the stem cell niche.
De Lisio M, Parise G. Exercise and hematopoietic stem and progenitor cells: protection, quantity, and function. Exerc Sport Rev 2013;41(2):116-22. on-line reference
4. Stem Cell Quiescence
Hematopoietic stem cells (HSCs) reside in hypoxic niches in the bone marrow. They can both self-renew (replicate themselves) and produce their progenitor cells, blood cells and immune cells. Resting quiescent stem cells in the hypoxic surroundings utilize primarily anaerobic glycolysis (similar to fasting or a ketogenic diet) for energy. This metabolic pathway maintains a functional quiescent state. When the HSCs exit from quiescence and rapidly proliferate and differentiate into different blood cell types, up-regulation of the energy production must meet the demand. If there is dysfunction in the metabolism, it can result in various blood disorders, including leukemia.
Hsu P, Qu CK. Metabolic plasticity and hematopoietic stem cell biology. Curr Opin Hematol 2013;20(4):289-94. on-line reference
5. Oxidative Stress
Reactive oxygen species (ROS) can be generated by mitochondrial dysfunction, exposure to radiation, or environmental damaging agents. Increases in ROS lead to oxidative stress and DNA damage. The authors provide research that oxidative stress leads to hematopoietic stem cell aging and eventual disease.
Richardson C, Yan S, Vestal CG. Oxidative stress, bone marrow failure, and genome instability in hematopoietic stem cells. Int J Mol Sci 2015;16(2):2366-85. on-line reference
6. Hematopoietic Stem Cell Aging
There is growing evidence that aging of the immune system, called immunosenescence, is initiated by hematopoietic stem cells. While this process used to be considered irreversible, there are factors being researched that may reverse some aspects of this aging process.
Geiger H, de Haan G, Florian MC. The Ageing haematopoietic stem cell compartment. Nat Rev Immunol 2013;13(5):376-89. on-line reference
