NF-kB in Stem Cells

During the development of the mammalian central nervous system (CNS), multipotent precursor cells (stem cells) undergo division, cell fate specification, and maturation. These neural stem cells (NSCs) are characterized by the ability to proliferate and to differentiate into multiple cell types, e.g. neurons or glial cells.

neural_stem_cells x600

Scheme of the differentiation pathways of neural stem cells

Embryonic and adult neural stem cells perform self-renewal or differentiate into more committed  progenitor cells. These common progenitors give rise to glial and neuronal precursors, which can terminally differentiate into neurons and glial cells. In contrast to neural stem cells, neuronal progenitors give rise to neuronal and not to glial progeny.

In pathological situations, such as brain inflammation, NSCs have been described to ameliorate the disease either due to increased proliferation and replacement of the degenerated tissue or due to secretion of protective cytokines.  Much of the inflammatory signal transduction can be considered as the innate immune response triggered by tumor necrosis factor (TNF), one of the crucial inflammation mediators and a well described activator of the transcription factor Nuclear Factor-kappaB (NF-kB).

We were able to demonstrate, that NF-kB and its target genes play a pivotal role in the regulation of neural stem cells biology. In particular, NF-kB regulates the TNF mediated proliferation of neural stem cells [1]. In in vitro cultures of NSC, TNF-a mediated NF-kB activation is responsible for fast re-aggregation of neurosphere cultures [2]. Importantly, a deregulation of the pathway leads to tumorigenic transformation of NSCs [3].

Furthermore we described for the first time, that MCP-1, a well known NF-kB target, efficiently regulates the migration of NSCs [4].

Currently, we are interested in the role of NF-kB in various aspects of the stem cell biology - proliferation, differentiation, migration  and potential transformation of `normal`stem cells into cancerous phenotype (reviewed in [5, 6] [7]).

 

[1]        D. Widera, I. Mikenberg, M. Elvers, C. Kaltschmidt, B. Kaltschmidt, Tumor necrosis factor alpha triggers proliferation of adult neural stem cells via IKK/NF-kB signaling, BMC Neurosci 7 (2006) 64.

[2]        D. Widera, I. Mikenberg, A. Kaus, C. Kaltschmidt, B. Kaltschmidt, Nuclear Factor-kappaB controls the reaggregation of 3D neurosphere cultures in vitro, Eur Cell Mater 11 (2006) 76-84; discussion 85.

[3]        A. Kaus, D. Widera, S. Kassmer, J. Peter, K. Zaenker, C. Kaltschmidt, B. Kaltschmidt, Neural stem cells adopt tumorigenic properties by constitutively activated NF-kB and subsequent VEGF up-regulation, Stem Cells Dev 19 (2010) 999-1015.

[4]        D. Widera, W. Holtkamp, F. Entschladen, B. Niggemann, K. Zanker, B. Kaltschmidt, C. Kaltschmidt, MCP-1 induces migration of adult neural stem cells, Eur J Cell Biol 83 (2004) 381-387.

[5]        D. Widera, C. Kaltschmidt, B. Kaltschmidt, NF-kB, Potential Role in Adult Neural Stem Cells, in: Hirokawa, Windhorst, Hirsch (Eds.), Encyclopedia of Neuroscience, Springer Verlag, Berlin, 2009, pp. 2862 - 2867.

[6]        D. Widera, I. Mikenberg, B. Kaltschmidt, C. Kaltschmidt, Potential role of NF-kB in adult neural stem cells: the underrated steersman?, Int J Dev Neurosci 24 (2006) 91-102.

[7]        D. Widera, A. Kaus, C. Kaltschmidt, B. Kaltschmidt, Neural stem cells, inflammation and NF-kB: basic principle of maintenance and repair or origin of brain tumours?, J Cell Mol Med 12 (2008) 459-470.