Normal Hematopoiesis Is a Balancing Act of Self-Renewal and Regeneration

Abstract

The hematopoietic system is highly organized to maintain its functional integrity and to meet lifelong organismal demands. Hematopoietic stem cells (HSCs) must balance selfrenewal with differentiation and the regeneration of the blood system. It is a complex balancing act between these competing HSC functions. Although highly quiescent at steady state, HSCs become activated in response to inflammatory cytokines and regenerative challenges. This activation phase leads to many intrinsic stresses such as replicative, metabolic, and oxidative stress, which can cause functional decline, impaired self-renewal, and exhaustion of HSCs. To cope with these insults, HSCs use both built-in and emergency-triggered stress-response mechanisms to maintain homeostasis and to defend against disease development. In this review, we discuss how the hematopoietic system operates in steady state and stress conditions, what strategies are used to maintain functional integrity, and how deregulation in the balance between self-renewal and regeneration can drive malignant transformation.

Stromal inflammation is a targetable driver of hematopoietic aging

“…To demonstrate the functional impact of age-related niche inflammation, we focused on IL-1, a well-known regulator of myeloid regeneration 6 . Chronic IL-1β exposure in young mice is known to mimic features of blood aging 38 , with myeloid cell expansion and decreased lymphopoiesis associated with anemia and thrombosis ( Extended Data Fig.…”

“…Aging also leads to major changes in bones and the marrow cavity, which together provide specialized niches for HSCs and hematopoietic progenitors 2–4 . Blood production is tailored in part by differential production of distinct HSC-derived MPP subsets with specific myeloid (MPP2, MPP3) and lymphoid (MPP4) lineage biases, which in turn give rise to an array of lineage-restricted progenitors and mature cells 5,6 . The niche and factors present in the marrow milieu, in particular pro-inflammatory cytokines, play important roles in controlling blood output by regulating the number and activation of HSCs, tuning the production and differentiation of lineage-biased and lineage-restricted progenitors, modulating stress hematopoiesis, and exerting context-dependent roles in leukemic transformation 3,4,6,7 .…”

RNA m6A Modification Plays a Key Role in Maintaining Stem Cell Function in Normal and Malignant Hematopoiesis

“…Hematopoietic homeostasis is maintained by rare multipotent hematopoietic stem cells (HSCs) via efficient self-renewal and differentiation into all lineage blood cells. This process is tightly controlled at multilayers such as the transcriptional and post-transcriptional levels (Orkin and Zon, 2008;Olson et al, 2020;Wilkinson et al, 2020). Alterations in these regulatory mechanisms affect the function of HSCs, and frequently cause hematologic diseases.…”

Hematopoietic regeneration under the spell of epigenetic-epitranscriptomic factors and transposable elements

“…Hematopoietic stem cells (HSCs) are maintained in quiescence in the bone marrow to safeguard their genomic integrity and protect themselves from exhaustion. Stress signals, including blood loss, pathogens, inflammation, metabolic stress and others, induce HSCs to exit quiescence, divide and replenish the hematopoietic system [1,2]. This regenerative response depends on the fast HSC adaptability and is subjected to multiple layers of control involving epigenetic and epitranscriptomic regulators, but also the activation of transposable elements [3,4].…”