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VASCULAR REGENERATION

Lymphatic-to-blood vessel transdifferentiation in zebrafish

Nature Cardiovascular Research volume 1, pages 539–541 (2022)Cite this article

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Blood vessels are thought to form either by de novo vasculogenesis or by angiogenesis from pre-existing blood vessels. Research now finds that anal fin blood vessels form by endothelial transdifferentiation from lymphatic vessels.

Endothelial cells are well known for their heterogeneity and plasticity under physiological and pathophysiological conditions. For example, there are several origins of lymphatic endothelial cells (LECs), and hybrid vessels that have markers of both lymphatic and blood vascular endothelial (BEC) have been described1,2. Although there is evidence that BECs can transdifferentiate into LECs under physiological conditions, the inverse process has not been described. In this week’s issue of Nature, Das et al.3 dispel this long-held belief and show that blood vessels in the zebrafish anal fin derive from pre-existing lymphatic vessels by transdifferentiation of LECs into blood vascular endothelium. This process happens during metamorphosis in zebrafish development, and it is recapitulated during the regeneration of anal fins after resection in adult fish. When the researchers prevented lymphatic development by using fish with ablation of the Flt4 (also known as Vegfr3) gene, the anal fins became vascularized by angiogenesis from the nearby blood vessels. However, in contrast to the vascular network formed by the LEC-to-BEC transdifferentiation, the vascular network formed by angiogenesis was functionally deficient as it was unable to support normal bone development in the anal fins. The blood vessels generated in anal fins in fish that lacked Flt4 exhibited continuous blood flow, unlike the blood vessels of lymphatic origin that were characterized by intermittent entry of red blood cells (RBCs), which is a hallmark of the specialized vascular compartment known as the secondary vascular system (SVS) in ray-finned fish.

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Fig. 1: Simplified schematics showing how the views on the vasculature of ray-finned fishes have evolved.

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Authors and Affiliations

  1. Drug Research Program, University of Helsinki, Helsinki, Finland

    Michael Jeltsch

  2. Individualized Drug Therapy, University of Helsinki, Helsinki, Finland

    Michael Jeltsch

  3. Wihuri Research Institute, Helsinki, Finland

    Michael Jeltsch & Kari Alitalo

  4. Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland

    Kari Alitalo

  5. Helsinki University Hospital, Helsinki, Finland

    Kari Alitalo

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  1. Michael Jeltsch
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  2. Kari Alitalo
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Correspondence to Kari Alitalo.

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The authors do not declare any conflict of interest.

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Jeltsch, M., Alitalo, K. Lymphatic-to-blood vessel transdifferentiation in zebrafish. Nat Cardiovasc Res 1, 539–541 (2022). https://doi.org/10.1038/s44161-022-00073-1

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