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Blood, 15 March 2005, Vol. 105, No. 6, pp. 2248.
Challenging the role of Notch in HSC biologyROBARTS RESEARCH INSTITUTE
Notch signaling is viewed as a potent regulator of mammalian hematopoietic stem cells (HSCs). Surprisingly, a study by Radtke's group demonstrates that donor or recipient mice with inactivated Notch1 or Jagged1 were capable of normal HSC reconstituting function. This observation challenges the essential nature of Notch signaling in homeostatic function of HSCs.
Mancini's group employs a sophisticated inducible Cre-loxP transgenic mouse system to specify and control the inactivation of Notch1 (N1), and/or its putative ligand, Jagged1 (J1). Mice with inactivated N1 or J1 had normal HSC function, and were capable of normal hematopoietic development and reconstitution of this function upon transplantation of HSCs into recipients. Importantly, this study not only addresses the autonomous role of J1-mediated Notch signaling among HSCs and progenitors, but also HSC interactions with the bone marrow microenvironment in recipients with inactivated J1 that retain a normal hematopoietic system after HSC transplantation.
The mechanisms that govern HSC biology remain elusive. However, independent categories that delineate signaling pathways and transcription factors that are essential versus those that augment existing HSC function are emerging. These categories may be related, but allow access to unique components of HSC behavior. Those that fall in the category of essential are likely to disrupt HSC function upon inactivation, and probably do not include J1-mediated Notch signaling or (as also demonstrated by Mancini's group) Caveats persist. In the case of such complex signaling pathways, inactivation studies capable of targeting specific signaling machinery are plagued by the lack of definitive evidence to exclude the pathway involvement due to potential compensatory mechanisms. For example, in the normal condition, the Notch pathway consists of more than 4 receptors and more than 5 ligands, whereas the Wnt pathway consists of more than 9 frizzled receptors and 12 ligands. To further complicate matters, these 2 pathways crosstalk, and since the interdependency is unknown, not only could other Notch-Notch ligand–mediated interactions compensate for inactivation of J1 or N1, it is also possible that Wnt signaling may rescue potential HSC deficiencies due to an absence of appropriate Notch signaling. It is likely that some level of certainty will be required to address these issues by evaluating other components of the targeted pathway and other crosstalking signaling pathways in HSCs after inactivation.
The study by Mancini et al embodies the power of such experimental approaches to test paradigms of HSC biology that evolve from the interpretation of other studies attempting to define a means to modulate HSCs. This study, and future studies like it, will assist in identifying additional questions to understand the elusive mechanisms that regulate HSCs. In the meantime, introduction of Notch and/or Wnt ligands during ex vivo culture of HSCs remains a possibility to augment HSC number, independent of evidence that supports an essential role of Notch or Wnt signaling in HSCs.
Related Article in Blood Online:
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| Copyright © 2005 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
-catenin–based signaling required for the Wnt pathway. Despite these observations, both Notch and Wnt signaling expand or augment baseline HSC function. 