Hematopoietic stem cell and multi lineage defects generated by constitutive β ‑catenin activation.
The continuous regeneration of blood cells depends on the unique ability of few hematopoietic stem cells (HSCs) to self-renew and to generate differentiated progeny of all blood cell lineages . A fundamental issue in hematopoiesis is to understand and therapeutically exploit the molecular mechanisms involved in the balance of self-renewal and lineage commitment of HSCs. Signaling through the Wnt pathway plays a key role in this process. Wnt proteins represent a large family of secreted signal proteins that can trigger at least three distinct intracellular pathways: the canonical Wnt– β ‑catenin pathway, the noncanonical Wnt – Ca 2+ pathway, and the Wnt – c‑Jun N‑terminal kinase (JNK) pathway. The central molecule in the canonical Wnt pathway is β ‑catenin, which directly mediates gene regulation at the level of transcription. The fact that β ‑catenin not only supports stem cells but also represents a major oncoprotein is of principal therapeutic importance.
Now, Marina Scheller (laboratory of Achim Leutz ) and colleagues have published a study aimed at understanding the effects of b ‑catenin activation in hematopoietic stem cells in mice (Nature Immunology, 03 September 2006 doi: 10.1038/ ni1387 ). The researchers show that excessive activation of canonical Wnt signaling causes multi-lineage differentiation block and compromises HSC biology. Conditional mouse genetics and transplantation assays were employed to demonstrate that constitutive activation of β ‑catenin blocks multi-lineage differentiation, leading to death. Blood cell depletion is accompanied by failure of HSCs to repopulate irradiated hosts and to differentiate into mature cells. Activation of β ‑catenin enforces cell cycle entry of HSCs, thus leading to exhaustion of the long-term stem cell pool. The results of the study suggest that fine-tuned Wnt signaling is essential for hematopoiesis and, thus, critical for therapeutic HSC expansion.
Contact:
Pamela Cohen
p.cohen@mdc-berlin.de
+49 30 9406 2121
