CXCL12 N-terminal end is sufficient to induce chemotaxis and proliferation of neural stem/progenitor cells

Abstract

Neural stem/progenitor cells (NSC) respond to injury after brain injuries secreting IL-1, IL-6, TNF-α, IL-4 and IL-10, as well as chemokine members of the CC and CXC ligand families. CXCL12 is one of the chemokines secreted at an injury site and is known to attract NSC-derived neuroblasts, cells that express CXCL12 receptor, CXCR4. Activation of CXCR4 by CXCL12 depends on two domains located at the N-terminal of the chemokine. In the present work we aimed to investigate if the N-terminal end of CXCL12, where CXCR4 binding and activation domains are located, was sufficient to induce NSC-derived neuroblast chemotaxis. Our data show that a synthetic peptide analogous to the first 21 amino acids of the N-terminal end of CXCL12, named PepC-C (KPVSLSYRCPCRFFESHIARA), is able to promote chemotaxis of neuroblasts in vivo, and stimulate chemotaxis and proliferation of CXCR4+ cells in vitro, without affecting NSC fate. We also show that PepC-C upregulates CXCL12 expression in vivo and in vitro. We suggest the N-terminal end of CXCL12 is responsible for a positive feedback loop to maintain a gradient of CXCL12 that attracts neuroblasts from the subventricular zone into an injury site.

SDF-1 and CXCR4 play an important role in adult SVZ lineage cell proliferation and differentiation

“…SDF-1/CXCR4 signaling regulates NPC migration, proliferation and survival (Filippo et al, 2013;Ruscher et al, 2013;Schwartz et al, 2012). These observations are 9 consistent with the fact that SDF-1 is pleiotropic and has been reported to inhibit proliferation and promote quiescence (Krathwohl and Kaiser, 2004).…”

SDF-1 overexpression by mesenchymal stem cells enhances GAP-43-positive axonal growth following spinal cord injury

“…The data from this study suggests that this cloned SDF-1␣ not only maintains chemotactic functions, but also can exert greater migratory effects on NSCs in vitro, when secreted at levels exceeding those from MSCs alone. Importantly, the N' terminus of SDF-1␣ was cloned without mutation, as manipulation of this region of the protein has been shown to be more sensitive to disrupting the chemotactic properties of these proteins (Filippo et al, 2013).…”

Regulation of Dipeptidyl Peptidase IV in the Post-stroke Rat Brain and In Vitro Ischemia: Implications for Chemokine-Mediated Neural Progenitor Cell Migration and Angiogenesis

“…However, new neurons/neuroblasts exhibit inhibited survival and migration, possibly due to insufficient levels of active SDF1 in the injured regions. Interestingly, N-terminal end of SDF1 is sufficient and required to induce chemotaxis and proliferation of neural stem/progenitor cells [24,69]. Although, pathophysiological significance of SDF1 cleavage in ischemic brain is not clear, presumably, excessive production of DPPIV through its proteolytic cleavage of N-terminal region of SDF1 inhibits SDF1 mediated functions.…”