Hematopoietic stem cell a reservoir of innate immune memory

Abstract

Hematopoietic stem cells (HSCs) are a rare, long-lived and multipotent population that give rise to majority of blood cells and some tissue-resident immune cells. There is growing evidence that inflammatory stimuli can trigger persistent reprogramming in HSCs that enhances or inhibits the cellular functions of these HSCs and their progeny in response to subsequent infections. This newly discovered property makes HSCs a reservoir for innate immune memory. The molecular mechanisms underlying innate immune memory in HSCs are similar to those observed in innate immune cells, although their full elucidation is still pending. In this review, we examine the current state of knowledge on how an inflammatory response leads to reprogramming of HSCs. Understanding the full spectrum of consequences of reshaping early hematopoiesis is critical for assessing the potential benefits and risks under physiological and pathological conditions.

Keywords: emergency hematopoiesis; epigenetic; hematopoietic stem and progenitor cells (HSPCs); inflammation; innate immune memory; metabolism; myelopoiesis.

Figure 1

Hematopoiesis during homeostasis and in response to an inflammatory environment. Hematopoietic stem cells (Lin-cKit+ sca-1+ FIt3- CD150+CD48-) are at the top of hematopoiesis and switch from the quiescent state (qHSC) to the activated state (aHSC) to meet the demand for mature cells. They differentiate into multipotent cells (MPP), which have a preference for differentiating into a specific cell lineage. Thus, MPP2 (Lin- cKit+ sca-1+ FIt3- CD150+ CD48+) are oriented towards the erythro-megakaryocytic lineage, MPP3 (Lin- cKit+ sca-1+ Fit3- CD150- CD48+) towards the myeloid lineage and MPP4 (Lin- cKit+ sca-1+ Flt3+) towards the lymphoid lineage. MPP differentiate into the precursors of the MEP (Lin- cKit+ sca-1- CD16/32-CD34-), GMP (Lin- cKit+ sca-1- CD16/32+ CD34+) and CLP (Lin- cKit+ sca-1- FIt3+ IL7R+) lineages, which eventually give rise to mature cells. In response to inflammatory stimuli, HSCs are strongly activated and the myeloid differentiation pathway is mainly favored.

Figure 2

Infection sensing of HSCs. Microbes or an inflammatory environment caused by lifestyle, disease or aging can be recognized by HSCs via receptors they express. The receptors are colored according to their expression levels observed by RNA-seq in HSCs. This sensing triggers a cascade of signaling pathways that lead to the expression of myeloid genes involved in myeloid differentiation or inflammation. The activation of HSCs is maintained for the duration of the stimulation. With chronic or repeated stimulation, HSCs show loss of function and exhaustion.

Figure 3

Innate immune memory programs triggered by acute and chronic inflammation. IIM is a defense mechanism of the body that provides greater protection against secondary insults thanks to epigenetic reprogramming that enables enhanced and/or dampened functionality of cells. In hematopoietic stem cells (HSCs), various IIM programs - trained immunity, priming or tolerance - can be induced depending on the context of the infection. In the bone marrow, the transient pro-inflammatory environment induced by acute stimulation leads to transient activation of HSCs but long-term trained immunity. Conversely, chronic stimulation maintains a pro-inflammatory environment that leads to sustained activation of HSCs and priming. In both cases, IIM leads to enhanced function upon second stimulation, while tolerance shows a dampened response. Although IIM provides clear protection against many secondary insults, it can also have unfavorable consequences for the organism.

Figure 4

Metabolic and Epigenetic Pathways involved in IIM: A Comparative Insight into HSPCs vs. Myeloid Cells. The initiation of mechanisms required for inducing innate immune memory depends on the duality of epigenetic and metabolic reprogramming of innate immune cells upon stimulation. During the initial challenge, the recognition of specific ligands by patter recognition receptors triggers a series of intracellular cascades, leading to the upregulation of various metabolic pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, and glutaminolysis. Metabolites produced from these processes, like fumarate and acetyl coenzyme A (acetyl-CoA), can activate or inhibit enzymes involved in remodeling the cell's epigenetic landscape, such as the histone demethylase lysine-specific demethylase 5 (KDM5) and histone acetyltransferases. This results in specific changes in the histone methylation and acetylation of genes involved in innate immune responses. This increases the accessibility of DNA to the transcriptional machinery and gene regulatory elements, as well as specific long non-coding RNAs, thereby promoting and facilitating enhanced gene transcription upon secondary stimulation of the cells.