Trends in Cell Biology
Volume 28, Issue 1, January 2018, Pages 58-66
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Review
Proinflammatory Signals as Fuel for the Fire of Hematopoietic Stem Cell Emergence

https://doi.org/10.1016/j.tcb.2017.08.003Get rights and content

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HSC specification occurs during early stages of embryonic development. A complex network of signals orchestrates this process. Attempts to replicate these signals in vitro to instruct embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) to produce bona fide HSCs have been unsuccessful to date.

Adult HSCs are armed with immune receptors (TLRs and NLRs) to sense infection and stress signals. They respond with changes in gene expression, producing large amounts of proinflammatory cytokines that contribute to myeloid differentiation and emergency hematopoiesis to fight the cause of infection.

Proinflammatory signals and immune cells are required to specify HSCs in the aseptic embryo. Translational use of these in vivo immunomodulators to in vitro protocols may improve efforts to generate functional HSCs.

Hematopoietic stem cells (HSCs) have the extraordinary ability to both self-renew and generate all mature blood cell lineages. The ability to produce or expand patient-derived HSCs in vitro would greatly improve the outcome for patients with blood disorders that are currently treated with allogeneic HSC transplantation. Many laboratories have been working to identify the signals required for HSC emergence in their native environments to apply this knowledge in vitro. Recently, several signals traditionally known to underlie classical inflammation have emerged as essential regulators of HSC development. In this review we synthesize the findings that have established inflammatory cues as key regulators of HSC development.

Section snippets

HSC Formation Requires a Complex Cocktail of Molecular Cues, Including Proinflammatory Signals

Stem cells (SCs) are undifferentiated cells with the extraordinary capabilities of both generating many different types of effector cells in a multicellular organism and regenerating themselves. These remarkable traits have led to the extensive study of SCs, with an ultimate goal of utilizing them to repair and replenish damaged tissues in patients. Among all SCs, HSCs are by far the most studied and the only ones utilized routinely in the clinic, for HSC transplantation (HSCT) therapies (see

The Signaling Basis of Classical Inflammation

Tissue disruption due to injury or pathogenic agents leads to the release of proinflammatory cytokines that result in classical inflammation. This process entails changes in gene expression and cellular function to eliminate the cause of the cellular injury and initiate tissue repair. It is surprising that the key pathways underlying the canonical responses to infection and inflammation are required to generate the founders of the adult hematopoietic system, since the emergence of HSCs from the

Adult HSCs Respond to Immunoregulators

Previously it was assumed that adult HSCs rarely divide and behave independently of extrinsic factors; however, it has become clear that HSCs respond dynamically to locally (niche/microenvironment) and distally (injury or infection) produced cytokines, including proinflammatory cytokines, chemokines, and PAMPs 10, 21, 22. Illustrative of such a response is the ability of HSCs to skew normal hematopoiesis towards myelopoiesis, often at the expense of lymphopoiesis and erythropoiesis, in a

Proinflammatory Cytokines as Key Regulators of HSC Development

Interestingly, the role of immunomodulators is not limited to adult HSC function. The first observations suggesting that proinflammatory pathways might be required to establish the hematopoietic system during embryogenesis in both vertebrates and invertebrates date from the late 1990s [32]. These studies linked the prototypical proinflammatory transcription factor NF-κB with the formation of the hematopoietic system (for a review see [16]). However, it was not until 10 years later that

Concluding Remarks

Proinflammatory signals have been classically believed to downregulate stem cell activity; however, this concept has been challenged in recent years due to accumulating evidence that proinflammatory signals positively regulate SCs in settings of tissue repair and regeneration [55]. HSCs are born in the developing embryo. The complex processes of tissue formation and regeneration after tissue damage frequently involve the same molecular signaling pathways 56, 57. It thus may be unsurprising that

Acknowledgments

This work was supported by Fundacion Seneca, Agencia Regional de Ciencia y Tecnologia de la Region de Murcia (19136/PD/13-N), and American Heart Association (16POST30690005) postdoctoral awards for R.E-P.

Glossary

Classical inflammation
a complex biological process in which a tissue disruptor (pathogen or injury) is sensed, typically by immune cells, leading to the production of proinflammatory cytokines that activate the immune system to eliminate the cause of the disruption. In addition, tissue-resident cells and endothelial cells are activated to restore healthy tissue.
Eicosanoids
lipids that act in the proximity of the producer cell to regulate inflammation.
Embryonic stem cells (ESCs)
cells obtained

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