Hematopoiesis - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 22

member SLAMF1 (SLAMF1 high HSCs), or CD150 (Table 2.1 ), possess a stronger
self-renewal potential, and predominate the stem cell pool in the aging body,
whereas those that generate lower levels of SLAMF1 (SLAMF1 low

HSCs) have a

balanced lineage output.
Hematopoiesis depends on hematopoietic stem cell survival, self-renewal, and
differentiation, hence mainly on the balance between quiescence (reserve) and cell
division (regeneration of its pool and blood tissue). Lifetime hematopoiesis indeed
relies on the capacity of hematopoietic stem cells to self-renew and to generate
blood cells according to the body's needs. Blood homeostasis, hence hematopoiesis,
requires long-term retention of hematopoietic stem cells in quiescence to maintain
hematopoietic regenerative capacity. In the absence of a need of strong blood
regeneration, the bone marrow, which is the site of blood cell formation from
hematopoietic stem cells, maintains the circulating cell pool because mature blood
cells continuously undergo senescence with a given degradation rate.
Tissue regeneration depends, at least partly, on stem cells, hence on their
metabolic regulation. Hematopoietic stem cells are highly sensitive to energetic and
oxidative stress; they shift between quiescence and proliferation according to the
context. Kinase STK11, or LKB1, and its substrate AMPK coordinate metabolism
with cell fate, thereby adapting cellular energetics with stem cell maintenance or
tissue regeneration. The primary function of LKB1 in adult tissues is its inhibition of
cell division, hence preventing tissue overgrowth. Enzyme LKB1 also controls cell
survival and proliferation, as well as mitochondrial function and energy homeostasis
in hematopoietic stem cells [ 42 ]. Inactivation of and deficiency in LKB1 in adult
mice causes loss of HSC quiescence and subsequent depletion of all hematopoietic
derived cells, as well as mitochondrial defects, alterations in lipid and nucleotide
metabolism, and depletion of cellular ATP [ 42 - 44 ]. Hematopoietic stem cells relies
more strongly on LKB1 for cell cycle regulation and survival than committed
hematopoietic progenitor and precursor cells [ 42 , 44 ]. However, LKB1 is needed
for HSC maintenance via AMPK-dependent and -independent mechanisms [ 42 , 43 ].
Metabolic sensor LKB1 indeed controls chromosome stability in HSCs via an
AMPK-independent process. The metabolic control in hematopoietic stem cells
yields an additional metabolic checkpoint of the cell division cycle. The bone
marrow niche controls by sending proper cues the activity of hematopoietic stem
cells during regenerative hematopoiesis.
The transcriptional regulation of cell quiescence relies on cell cycle regulators
(e.g., P53, retinoblastoma protein, cyclin-D, and cyclin-dependent kinase inhibitors
CKI1a and CKI1b) and factors with specific functions in hematopoietic stem
cells (e.g., early growth response factor EGR1, forkhead box protein FoxO, DNA
sequence GATA-binding protein GATA2, growth factor-independent transcription
repressor GFI1, and Runx1). 2 The transcription factor, nuclear receptor-related

2 Cell quiescence is associated with: (1) downregulation of cyclin-D1; (2) upregulation of cyclin-
dependent kinase inhibitors CKI1a and CKI2a; (3) action of T-cell-intrinsic quiescence factor
FoxO1; and (4) activation of P38MAPK [ 45 ]. Factor FoxO1 maintains cell quiescence and impedes
T-cell activation by self-antigens, but does not prevent polyclonal T-cell activation. Polyclonal