Hepatic Leukemia Factor Maintains Quiescence of Hematopoietic Stem Cells and Protects the Stem Cell Pool during Regeneration

Abstract In this issue’s Blood Advances Talk, Lapidot and Golan discuss how changes in daily light regulate hematopoiesis. This fascinating mechanism helps control the process of maintaining the hematopoietic stem cell pool while promoting sufficient differentiation to supply adequate numbers of functional blood cells. We hope you enjoy listening to this interesting topic.

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Mitochondria in the maintenance of hematopoietic stem cells: new perspectives and opportunities

Blood ◽

10.1182/blood-2018-10-808873 ◽

2019 ◽

Vol 133 (18) ◽

pp. 1943-1952 ◽

Cited By ~ 16

Author(s):

Marie-Dominique Filippi ◽

Saghi Ghaffari

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Blood Cells ◽

Self Renewal ◽

Hematopoietic Stem ◽

Hematopoietic System ◽

Cellular Energy ◽

Cell Pool ◽

Stem Cell Pool

Abstract The hematopoietic system produces new blood cells throughout life. Mature blood cells all derived from a pool of rare long-lived hematopoietic stem cells (HSCs) that are mostly quiescent but occasionally divide and self-renew to maintain the stem cell pool and to insure the continuous replenishment of blood cells. Mitochondria have recently emerged as critical not only for HSC differentiation and commitment but also for HSC homeostasis. Mitochondria are dynamic organelles that orchestrate a number of fundamental metabolic and signaling processes, producing most of the cellular energy via oxidative phosphorylation. HSCs have a relatively high amount of mitochondria that are mostly inactive. Here, we review recent advances in our understanding of the role of mitochondria in HSC homeostasis and discuss, among other topics, how mitochondrial dynamism and quality control might be implicated in HSC fate, self-renewal, and regenerative potential.

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Genetic control of hematopoietic stem cell frequency in mice is mostly cell autonomous

Blood ◽

10.1182/blood.v95.7.2446 ◽

2000 ◽

Vol 95 (7) ◽

pp. 2446-2448 ◽

Cited By ~ 33

Author(s):

Christa E. Müller-Sieburg ◽

Rebecca H. Cho ◽

Hans B. Sieburg ◽

Sergey Kupriyanov ◽

Roy Riblet

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Compartment ◽

Cell Frequency ◽

Hematopoietic Stem ◽

Stem Cell Compartment ◽

Cell Pool ◽

The Difference ◽

Extrinsic Effects ◽

Stem Cell Pool

Abstract Previously we reported that the size of the stem cell compartment (measured as LTC-IC) is 11-fold greater in DBA/2 than in C57BL/6 mice, and we identified genes that regulate the size of the stem cell pool. To determine whether stem cell intrinsic or extrinsic events account for these differences, we created chimeras by aggregating morulae from the strains C57BL/6 and DBA/2. In these chimeras stem cells of both genotypes are exposed to a common mixed environment. Thus, an equalization of stem cell frequencies is expected if stem cell extrinsic effects dominate. Conversely, the parental ratio of LTC-IC should be preserved if the regulation is stem cell autonomous. For each chimera, individual LTC-IC were genotyped on the clonal levels by analyzing their progeny. We found that most of the difference that regulates the size of the stem cell compartment was intrinsic.

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Genetic control of hematopoietic stem cell frequency in mice is mostly cell autonomous

Blood ◽

10.1182/blood.v95.7.2446.007k13_2446_2448 ◽

2000 ◽

Vol 95 (7) ◽

pp. 2446-2448 ◽

Cited By ~ 1

Author(s):

Christa E. Müller-Sieburg ◽

Rebecca H. Cho ◽

Hans B. Sieburg ◽

Sergey Kupriyanov ◽

Roy Riblet

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Compartment ◽

Cell Frequency ◽

Hematopoietic Stem ◽

Stem Cell Compartment ◽

Cell Pool ◽

The Difference ◽

Extrinsic Effects ◽

Stem Cell Pool

Previously we reported that the size of the stem cell compartment (measured as LTC-IC) is 11-fold greater in DBA/2 than in C57BL/6 mice, and we identified genes that regulate the size of the stem cell pool. To determine whether stem cell intrinsic or extrinsic events account for these differences, we created chimeras by aggregating morulae from the strains C57BL/6 and DBA/2. In these chimeras stem cells of both genotypes are exposed to a common mixed environment. Thus, an equalization of stem cell frequencies is expected if stem cell extrinsic effects dominate. Conversely, the parental ratio of LTC-IC should be preserved if the regulation is stem cell autonomous. For each chimera, individual LTC-IC were genotyped on the clonal levels by analyzing their progeny. We found that most of the difference that regulates the size of the stem cell compartment was intrinsic.

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Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size

Journal of Experimental Medicine ◽

10.1084/jem.20041992 ◽

2005 ◽

Vol 201 (11) ◽

pp. 1781-1791 ◽

Cited By ~ 451

Author(s):

Sebastian Stier ◽

Yon Ko ◽

Randolf Forkert ◽

Christoph Lutz ◽

Thomas Neuhaus ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Stem Cell Niche ◽

Regulatory Element ◽

Cell Number ◽

Hematopoietic Cell ◽

Hematopoietic Stem ◽

Cell Pool ◽

Cell Niche ◽

Stem Cell Pool

Stem cells reside in a specialized niche that regulates their abundance and fate. Components of the niche have generally been defined in terms of cells and signaling pathways. We define a role for a matrix glycoprotein, osteopontin (OPN), as a constraining factor on hematopoietic stem cells within the bone marrow microenvironment. Osteoblasts that participate in the niche produce varying amounts of OPN in response to stimulation. Using studies that combine OPN-deficient mice and exogenous OPN, we demonstrate that OPN modifies primitive hematopoietic cell number and function in a stem cell–nonautonomous manner. The OPN-null microenvironment was sufficient to increase the number of stem cells associated with increased stromal Jagged1 and Angiopoietin-1 expression and reduced primitive hematopoietic cell apoptosis. The activation of the stem cell microenvironment with parathyroid hormone induced a superphysiologic increase in stem cells in the absence of OPN. Therefore, OPN is a negative regulatory element of the stem cell niche that limits the size of the stem cell pool and may provide a mechanism for restricting excess stem cell expansion under conditions of niche stimulation.

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Nicotinamide riboside attenuates age-associated metabolic and functional changes in hematopoietic stem cells

Nature Communications ◽

10.1038/s41467-021-22863-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Xuan Sun ◽

Benjamin Cao ◽

Marina Naval-Sanchez ◽

Tony Pham ◽

Yu Bo Yang Sun ◽

...

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Network Size ◽

Vitamin B3 ◽

Hematopoietic Stem ◽

Mitochondrial Mass ◽

Functional Changes ◽

Nicotinamide Riboside ◽

Cell Pool ◽

Stem Cell Pool

AbstractWith age, hematopoietic stem cells (HSC) undergo changes in function, including reduced regenerative potential and loss of quiescence, which is accompanied by a significant expansion of the stem cell pool that can lead to haematological disorders. Elevated metabolic activity has been implicated in driving the HSC ageing phenotype. Here we show that nicotinamide riboside (NR), a form of vitamin B3, restores youthful metabolic capacity by modifying mitochondrial function in multiple ways including reduced expression of nuclear encoded metabolic pathway genes, damping of mitochondrial stress and a decrease in mitochondrial mass and network-size. Metabolic restoration is dependent on continuous NR supplementation and accompanied by a shift of the aged transcriptome towards the young HSC state, more youthful bone marrow cellular composition and an improved regenerative capacity in a transplant setting. Consequently, NR administration could support healthy ageing by re-establishing a more youthful hematopoietic system.

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Genetic control of the frequency of hematopoietic stem cells in mice: mapping of a candidate locus to chromosome 1.

Journal of Experimental Medicine ◽

10.1084/jem.183.3.1141 ◽

1996 ◽

Vol 183 (3) ◽

pp. 1141-1150 ◽

Cited By ~ 88

Author(s):

C E Müller-Sieburg ◽

R Riblet

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Hematopoietic Stem Cells ◽

Inbred Strains ◽

Cell Number ◽

Chromosome 1 ◽

Cell Frequency ◽

Candidate Locus ◽

Hematopoietic Stem ◽

Differentiation And Proliferation

The genetic elements that govern the differentiation and proliferation of hematopoietic stem cells remain to be defined. We describe here marked strain-specific differences in the frequency of long-term culture-initiating cells (LTC-IC) in the bone marrow of different strains of mice. Mice of C57Bl/6 background showed the lowest levels of stem cells in marrow, averaging 2.4 +/- .06 LTC-IC/10(5) cells, BALB/c is intermediate (9.1 +/- 4.2/10(5) cells), and DBA/2 mice contained a 11-fold higher frequency of LTC-IC (28.1 +/- 16.5/10(5) cells) than C57Bl/6 mice. The genetic factors affecting the size of the stem cell pool were analyzed in the C57Bl/6 X DBA/2 recombinant inbred strains; LTC-IC frequencies ranged widely, indicating that stem cell frequencies are controlled by multiple genes. Quantitative trait linkage analysis suggested that two loci that have major quantitative effects are located on chromosome 1 near Adprp and Acrg, respectively. The mapping of the locus near Adprp was confirmed by finding an elevated stem cell frequency in B6.C-H25, a C57Bl/6 congenic strain that carries a portion of chromosome 1 derived from BALB/c mice. We have named this gene Scfr1 (stem cell frequency regulator 1). The allelic forms of this gene may be an important predictor of stem cell number and thus would be useful for evaluating cell sources in clinical stem cell transplantation.

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