Blocking Kallikrein 6 promotes developmental myelination

Abstract

Kallikrein related peptidase 6 (Klk6) is a secreted serine protease highly expressed in oligodendrocytes and implicated in demyelinating conditions. To gain insights into the significance of Klk6 to oligodendrocyte biology, we investigated the impact of global Klk6 gene knockout on CNS developmental myelination using the spinal cord of male and female mice as a model. Results demonstrate that constitutive loss of Klk6 expression accelerates oligodendrocyte differentiation developmentally, including increases in the expression of myelin proteins such as MBP, PLP and CNPase, in the number of CC-1+ mature oligodendrocytes, and myelin thickness by the end of the first postnatal week. Co-ordinate elevations in the pro-myelinating signaling pathways ERK and AKT, expression of fatty acid 2-hydroxylase, and myelin regulatory transcription factor were also observed in the spinal cord of 7d Klk6 knockouts. LC/MS/MS quantification of spinal cord lipids showed sphingosine and sphingomyelins to be elevated in Klk6 knockouts at the peak of myelination. Oligodendrocyte progenitor cells (OPCs)-derived from Klk6 knockouts, or wild type OPCs-treated with a Klk6 inhibitor (DFKZ-251), also showed increased MBP and PLP. Moreover, inhibition of Klk6 in OPC cultures enhanced brain derived neurotrophic factor-driven differentiation.Altogether, these findings suggest that oligodendrocyte-derived Klk6 may operate as an autocrine or paracrine rheostat, or brake, on pro-myelinating signaling serving to regulate myelin homeostasis developmentally and in the adult. These findings document for the first time that inhibition of Klk6 globally, or specifically in oligodendrocyte progenitors, is a strategy to increase early stages of oligodendrocyte differentiation and myelin production in the CNS.

Sevoflurane causes cognitive impairment by inducing iron deficiency and inhibiting the proliferation of neural precursor cells in infant mice

“…Myelin sheath played an important role in learning and memory 6 . MBP, which mainly arose from the gene in the oligodendrocyte, was essential to the formation of the multilamellar myelin sheath of the mammalian central nervous system (CNS), 18 and CC‐1 was an important marker protein for oligodendrocyte labeling 19 …”

“…6 MBP, which mainly arose from the gene in the oligodendrocyte, was essential to the formation of the multilamellar myelin sheath of the mammalian central nervous system (CNS), 18 and CC-1 was an important marker protein for oligodendrocyte labeling. 19 In order to investigate the relationship between cognitive deficiency and myelin sheath formation, as well as the number of oligodendrocytes, we detected the expression of MBP and the number of CC-1 + cells. We found that Sev dramatically downregulated the MBP expression in cortex (68.60% ± 4% vs. 49.9 ± 6%, p = 0.0298, In order to further study the effect of Sev on myelin formation, TME was used to detect the myelin morphology of cortical and hippocampal tissues, and the results showed that the g ratio of cortical and hippocampal myelin increased, which meant that Sev caused the reduction of myelin thickness, as shown in Figure 3.…”

Chronic changes in oligodendrocyte sub‐populations after middle cerebral artery occlusion in neonatal mice

“…It is also possible paracrine factors produced by more mature oligodendrocytes in the ipsilateral striatum influence progenitor cells. The reactive cell cluster over expresses Klk6 , which has been shown to limit OPC differentiation into myelinating cells (Yoon et al, 2022). On the other hand, reactive cells and ipsilateral MFOL/MOL cells have significantly upregulated expression of Apoe , and ApoE is known to promote oligodendrocyte differentiation (Gan et al, 2011).…”

Chronic Changes In Oligodendrocyte Sub-Populations After Middle Cerebral Artery Occlusion in Neonatal Mice

“…It is also possible paracrine factors produced by more mature oligodendrocytes in the ipsilateral striatum influence progenitor cells. The reactive cell cluster over expresses Klk6 , which has been shown to limit OPC differentiation into myelinating cells[81]. On the other hand, reactive cells and ipsilateral MFOL/MOL cells have significantly upregulated expression of Apoe , and ApoE is known to promote oligodendrocyte differentiation[82].…”