Megakaryocytes promote murine osteoblastic HSC niche expansion and stem cell engraftment after radioablative conditioning

Olson, Timothy S.; Caselli, Anna; Otsuru, Satoru; Hofmann, Ted J.; Williams, Richard; Paolucci, Paolo; Dominici, Massimo; Horwitz, Edwin M.

doi:10.1182/blood-2012-10-463414

Cited by 140 publications

(126 citation statements)

References 38 publications

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“…[55][56][57][58] Two recent studies 59,60 have demonstrated that megakaryocytes likely contribute to the HSC niche because in vivo megakaryocyte ablation results in a loss of HSC quiescence. Because HSCs are proximal to megakaryocytes in the bone marrow and because BLOOD, 10 MARCH 2016 x VOLUME 127, NUMBER 10 EARLY STEM CELL-TO-MEGAKARYOCYTE TRANSITION 1245…”

Section: Megakaryocytes In the Hematopoietic Stem Cell Nichementioning

confidence: 99%

Hematopoietic stem/progenitor cell commitment to the megakaryocyte lineage

Woolthuis¹,

Park

2016

Blood

127

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The classical model of hematopoiesis has long held that hematopoietic stem cells (HSCs) sit at the apex of a developmental hierarchy in which HSCs undergo long-term self-renewal while giving rise to cells of all the blood lineages. In this model, self-renewing HSCs progressively lose the capacity for self-renewal as they transit into short-term self-renewing and multipotent progenitor states, with the first major lineage commitment occurring in multipotent progenitors, thus giving rise to progenitors that initiate the myeloid and lymphoid branches of hematopoiesis. Subsequently, within the myeloid lineage, bipotent megakaryocyte-erythrocyte and granulocyte-macrophage progenitors give rise to unipotent progenitors that ultimately give rise to all mature progeny. However, over the past several years, this developmental scheme has been challenged, with the origin of megakaryocyte precursors being one of the most debated subjects. Recent studies have suggested that megakaryocytes can be generated from multiple pathways and that some differentiation pathways do not require transit through a requisite multipotent or bipotent megakaryocyte-erythrocyte progenitor stage. Indeed, some investigators have argued that HSCs contain a subset of cells with biased megakaryocyte potential, with megakaryocytes directly arising from HSCs under steady-state and stress conditions. In this review, we discuss the evidence supporting these nonclassical megakaryocytic differentiation pathways and consider their relative strengths and weaknesses as well as the technical limitations and potential pitfalls in interpreting these studies. Ultimately, such pitfalls will need to be overcome to provide a comprehensive and definitive understanding of megakaryopoiesis.

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Section: Megakaryocytes In the Hematopoietic Stem Cell Nichementioning

confidence: 99%

Hematopoietic stem/progenitor cell commitment to the megakaryocyte lineage

Woolthuis¹,

Park

2016

Blood

127

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“…52 TPO administration before TBI enhances megakaryocyte-induced promotion of HSC engraftment. 53 One study showed that TPO can activate NF-kB in megakaryocytes. 54 It is intriguing that the same signaling pathway involving Iex-1, NF-kB, and Erk activation could be triggered by Mpl/TPO to protect both HSCs and megakaryocytes from TBI.…”

Section: Kitmentioning

confidence: 99%

Thrombopoietin promotes NHEJ DNA repair in hematopoietic stem cells through specific activation of Erk and NF-κB pathways and their target, IEX-1

Laval

Pawlikowska

Barbieri

et al. 2014

Blood

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Key Points• TPO specifically activates Erk and NF-kB pathways in hematopoietic stem and progenitor cells.• Erk and NF-kB cooperate to trigger their common target, Iex-1, and DNA-PKdependent NHEJ activation in HSPCs upon irradiation.Loss of hematopoietic stem cell (HSC) function and increased risk of developing hematopoietic malignancies are severe and concerning complications of anticancer radiotherapy and chemotherapy. We have previously shown that thrombopoietin (TPO), a critical HSC regulator, ensures HSC chromosomal integrity and function in response to g-irradiation by regulating their DNA-damage response. TPO directly affects the double-strand break (DSB) repair machinery through increased DNA-protein kinase (DNA-PK) phosphorylation and nonhomologous end-joining (NHEJ) repair efficiency and fidelity. This effect is not shared by other HSC growth factors, suggesting that TPO triggers a specific signal in HSCs facilitating DNA-PK activation upon DNA damage. The discovery of these unique signaling pathways will provide a means of enhancing TPO-desirable effects on HSCs and improving the safety of anticancer DNA agents. We show here that TPO specifically triggers Erk and nuclear factor kB (NF-kB) pathways in mouse hematopoietic stem and progenitor cells (HSPCs). Both of these pathways are required for a TPO-mediated increase in DSB repair. They cooperate to induce and activate the early stress-response gene, Iex-1 (ier3), upon DNA damage. Iex-1 forms a complex with pERK and the catalytic subunit of DNA-PK, which is necessary and sufficient to promote TPO-increased DNA-PK activation and NHEJ DSB repair in both mouse and human HSPCs. (Blood. 2014;123(4):509-519)

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“…After transplantation, HSCs home to Mk-rich endosteal areas [12][13][14] , and host Mk facilitate donor HSC engraftment after lethal irradiation 13 . In addition, co-culture with Mk slightly increased HSC numbers ex vivo 14 .…”

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confidence: 99%