In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 2 ( 2013-01-08)
Abstract:
The function of the Hedgehog-Notch-Scl axis in endothelial-to-hematopoietic conversion provides useful insight into the origins of vertebrate hematopoiesis; however, many aspects of the endothelial-to-hematopoietic transition are still unknown. One broad question is what combination of transcription factors is required to induce hematopoiesis from endothelial cells. A recent study noted that VE-cadherin endothelial cells are heterogeneous in that distinct populations give rise to erythroid/myeloid progenitors and hematopoietic stem cells ( 5 ). Future studies will likely focus on this heterogeneity in an attempt to fine-tune the subpopulation of VE-cadherin needed for the generation of hematopoietic stem cells for therapeutic approaches. The long-term goal would be to derive hematopoietic stem cells using patient-specific pluripotent stem cells for bone marrow transplantation in individuals without a matched donor. These approaches revealed that Hedgehog signaling is required for the generation of VE-cadherin–positive endothelial cells that can give rise to hematopoietic cells ( Fig. P1 ), thus providing the link between endothelial and hematopoietic development. In this regard, Hedgehog plays a functionally redundant role with the Notch signaling pathway, which has previously been shown to promote arterial specification in zebrafish embryos ( 4 ). Moreover, the transcription factor stem cell leukemia (Scl) can compensate for the loss of Hedgehog or Notch signaling during the endothelial-to-hematopoietic transition. The redundancy of Hedgehog and Notch and the potent effect of Scl in converting endothelial cells into hematopoietic cells were confirmed using zebrafish embryos in which the ectopic expression of Scl overcame dual inhibition of Hedgehog and Notch and rescued the expression of the prototypical hemogenic endothelial marker Runx1. In this scenario, endothelial cells did not need to form functional vessels for Scl to exert its effect. To study the role of Hedgehog signaling in hematopoiesis, we first induced mouse ES cells to become hematopoietic cells while altering components of the Hedgehog pathway to measure the effect on hematopoietic output and quantity of VE-cadherin–positive endothelial cells. We next dissected the hematopoietic compartments in the mouse embryo, such as the yolk sac and the aortic trunk, and assessed the effect of altered Hedgehog signaling on hematopoietic output. We also altered Hedgehog signaling in developing zebrafish embryos and assessed the changes in the level of gene expression associated with hematopoiesis. We took these three approaches, because each model system has its advantages and disadvantages. We used developing mouse ES cells to dissect signaling pathway components in large quantities and avoided confounders, such as early embryo lethality and cardiovascular deformities. Using this information, we were able to dissect the same pathways in mouse and zebrafish embryos. Zebrafish embryos finally allowed us to visualize the anatomical relationship between angioblasts and their subsequent differentiation into hematopoietic cells. Here, we studied the Hedgehog signaling pathway, which plays a role in vessel remodeling and is implicated in hematopoiesis. Research in this area is hampered, because transgenic mice defective in Hedgehog signaling die before birth. For example, mouse embryos that lack Hedgehog signaling fail to form a functioning aorta and show arrest around embryonic day 10 ( 2 ). Interestingly, Hedgehog signaling is not required in hematopoietic cells in adults ( 3 ). These prior observations led us to hypothesize that endothelial cells respond to Hedgehog signaling, and perhaps through this process, the Hedgehog pathway contributes to the endothelial-to-hematopoietic transition. Hematopoietic cells arise in many compartments in the developing embryo before they migrate to the bone marrow in the newborn, where they will continue to regenerate blood cells throughout their lifespan. In the developing mouse embryo, these hematopoietic compartments include extraembryonic tissues, such as the yolk sac and placenta, and embryonic compartments, such the dorsal aorta and fetal liver. Although it is unclear exactly how hematopoietic cells eventually populate the bone marrow, evidence suggests that adult hematopoietic cells transition through an endothelial intermediate, and the origins of adult hematopoiesis are in these endothelial cells ( 1 ). These endothelial cells express vascular endothelial cadherin (VE-cadherin), which is important for vascular integrity at cell–cell junctions, particularly in newly formed vessels. When Chen et al. ( 1 ) labeled cells in the developing mouse embryo, which were positive for VE-cadherin, they found that virtually all hematopoietic cells in the adult retained this label. The molecular events that modulate the transition of endothelial cells to hematopoietic cells are poorly understood. Understanding how adult hematopoietic cells arise from endothelial cells in the embryo may facilitate the generation of hematopoietic progenitors in vitro. These cells might serve as alternatives to donor-derived bone marrow transplantation to treat hematopoietic diseases, such as refractory leukemias.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1214361110
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2013
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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