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Page 2 of 12 Solimando et al. J Cancer Metastasis Treat 2022;8:9 https://dx.doi.org/10.20517/2394-4722.2021.166

out that the hematopoietic niches’ inflammatory stimulation may affect differentiation patterns and the function of
downstream cells.

Keywords: Hematopoietic niche, immune system, inflammation, tumor microenvironment

INTRODUCTION
A bone marrow niche can be streamlined as a narrow environment that guarantees the preservation and
modulation of the cell stemness. A simplified overview of the bone marrow microenvironment can be
sketched around the hematopoietic stem cell (HSC), with quiescent characteristics, capable of self-renewal
regulated by multiple niches. One niche is classified as endosteal niche, comprising the bone and several
multiple different cell types responsible for the maintenance of the bone and the maintenance of the
[1,2]
hematopoiesis . The perivascular niche also includes multiple and different nursing cells regulating the
hematopoiesis in direct crosstalk with the megakaryocytes, macrophages, and endothelial cells that act as
[3,4]
gatekeepers for the immune cells . The innervation and the immune cells are actively fueling the neural
niche, regulating the hematopoiesis via the mesenchymal stromal cells, which altogether lead to the
maintenance of normal hematopoiesis and homeostasis of the blood system . Moreover, the erythroblastic
[5,6]
island represents a fundamental niche where different stages of red blood progenitors mature over time
until they become enucleated cells, subject to the phagocytic process .
[7]

From this standpoint, inflammation, especially in its chronic phase, can be tightly connected to the normal
process of aging, being defined as inflammaging . A subclinical status of inflammation parallels an
[8,9]
increase in visceral body fat over time, leading to the recruitment of blood monocytes and polarization to
M1 macrophages, which are even more inflammatory, resulting in an increased production of
proinflammatory cytokines . On the other hand, both the muscle mass and the anti-inflammatory
[10]
myokines decrease, causing an increased inflammatory state. Collectively, the red marrow converts to fatty
marrow, actively taking part in the systemic inflammaging [11,12] . Within the bone marrow, a multipotent
stem cell-like cell can give rise to osteoblast and adipocytes under normal conditions, being also crucial to
regulated hematopoiesis : the state of aging can be mimicked in a mouse model by a high-fat diet, where
[12]
the multipotent stem cell-like population tends to differentiate into adipocytes, and there is less
differentiation into osteoblasts, leading to increased levels of DPP4, which, when inhibited, orchestrates a
more regenerative environment . A decreased bone healing mirrors the increased fat, being an underlying
[12]
cause of the defective hematopoiesis and the lack of maintenance of HSC. Thus, chronic inflammation
affects the balanced lineage output during the physiologic homeostasis that, in step with aging and disease,
leads to an impaired HSC self-renewal, with increased myelopoiesis . Chronic inflammation can be
[13]
considered not only as a chronic inflammatory disease but also as an aging-mediated process. Thus, HSC
can prime a decreased lymphopoiesis and reduced erythropoiesis. Furthermore, these niche dysfunctions
and stressors (i.e., reactive oxygen species and acquired mutations) can drive clonal hematopoiesis and a
[13]
malignant transformation . The niche dysfunction can be crucial in the development of full-blown
leukemia . Clonal hematopoiesis in an average individual with unremarkable hemogram and no evidence
[14]
of hematologic disease is known as clonal hematopoiesis of indeterminate potential (CHIP) and is also
known as clonal hematopoiesis of aging, being a common age-related condition .
[15]

ETIOLOGY AND BIOLOGY OF CLONAL HEMATOPOIESIS
The hematopoietic system, being probably one of the most proliferative tissues in the body, is
physiologically correlated with a high mutational rate. DNA-polymerase can lead to mutations in the most
proliferative progenitors and not retained in the progeny. Nonetheless, the mutation sometimes happens in