p57Kip2 regulates embryonic blood stem cells by controlling sympathoadrenal progenitor expansion

Kapeni, C. et al. (2022) p57Kip2 regulates embryonic blood stem cells by controlling sympathoadrenal progenitor expansion. Blood, 140(5), pp. 464-477. (doi: 10.1182/blood.2021014853) (PMID:35653588)

Abstract

Hematopoietic stem cells (HSCs) are of major clinical importance, and finding methods for their in vitro generation is a prime research focus. We demonstrate here that the cell cycle inhibitor p57Kip2/Cdkn1c limits the number of emerging HSCs by restricting the size of the sympathetic nervous system (SNS) and the amount of HSC-supportive catecholamines secreted by these cells. This regulation occurs at the SNS progenitor level and is in contrast to the cell-intrinsic function of p57Kip2 in maintaining adult HSCs, highlighting profound differences in cell cycle requirements of adult HSCs compared with their embryonic counterparts. Furthermore, this effect is specific to the aorta-gonads-mesonephros (AGM) region and shows that the AGM is the main contributor to early fetal liver colonization, as early fetal liver HSC numbers are equally affected. Using a range of antagonists in vivo, we demonstrate a requirement for intact b2-adrenergic signaling for SNS-dependent HSC expansion. To gain further molecular insights, we have generated a single-cell RNA-Seq dataset of all Ngfr+ sympathoadrenal cells around the dorsal aorta to dissect their differentiation pathway. Importantly, this not only defined the relevant p57Kip2-expressing SNS progenitor stage, but also revealed that some neural crest cells, upon arrival at the aorta, are able to take an alternative differentiation pathway, giving rise to a subset of ventrally restricted mesenchymal cells that express important HSC-supportive factors. Neural crest cells thus appear to contribute to the AGM HSC niche via two different mechanisms: SNS-mediated catecholamine secretion and HSC-supportive mesenchymal cell production.

• Item Type: Articles
• Additional Information: Core facilities at the Edinburgh Centre for Regenerative Medicine were supported by centre grant MR/K017047/1. This work was funded by the National Health and Medical Research Council of Australia (J.E.P. 1102589; and V.C. 1061593), a Bloodwise Bennett Senior Fellowship (10015 to K.O.) and the Kay Kendall Leukaemia Fund (to K.O.). This research was also funded in part by the Wellcome Trust and the UKRI Medical Research Council.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Kirschner, Dr Kristina
• Authors: Kapeni, C., Nitsche, L., Kilpatrick, A. M., Wilson, N. K., Xia, K., Mirshelar-Syahkal, B., Chandrakanthan, V., Malouf, C., Pimanda, J. E., Gottgens, B., Kirschner, K., Tomlinson, S., and Ottersbach, K.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Blood
• Publisher: American Society of Hematology
• ISSN: 0006-4971
• ISSN (Online): 1528-0020
• Published Online: 02 June 2022
• Copyright Holders: Copyright © 2022 American Society of Hematology
• First Published: First published in Blood 14095): 464-477
• Publisher Policy: Reproduced under a Creative Commons License