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Page 14 of 19 Mondal et al. Neuroimmunol Neuroinflammation 2018;5:34 I http://dx.doi.org/10.20517/2347-8659.2018.13

myelosuppression , suggesting that the quiescence of HSCs is closely associated with the protection
[28]
of the HSC pool from the various stresses induced by myelotoxic insults. However, precise regulatory
mechanisms of niche cell-HSCs remain elusive.

Ang-1 expressed by niche cell is one of the indispensable interacting molecules which function as an
autocrine activating factor for Tie-2 signaling in HSCs and their interaction activates β1-integrin and
N-cadherin, enhances quiescent state and facilitates long-term repopulating activity of HSCs by facilitating
induced adhesion to bone and homing during the physiological crisis. The critical regulatory role of Ang-1/
Tie-2 signaling in the maintenance of HSCs quiescence and promoting their adhesion to bone marrow
niche, resulting in protection of HSCs compartment from myelosuppressive insults has been documented
before . Furthermore, the mechanistic insight of this protective interaction against apoptosis by activating
[28]
the PI3K pathway has also been addressed . We have also documented the inhibitory role of T11TS on
[85]
glioma mediated pro-angiogenic Ang-1/Tie-2 signaling within brain endothelial cells ultimately restraining
pro-tumorigenic angiogenesis in rodent glioma model . Although the mechanism through which glioma
[86]
modulated activation of Ang-1/Tie-2 signaling within bone marrow niche and their correlation with
gliomagenic global immune suppression remain to be elucidated, we hypothesize that gliomagenic up
regulation of Ang-1/Tie-2 interaction disrupts the normal hematopoietic synchrony and ultimately affect
the lymphohematopoiesis.

Over expression of Ang-1 cells at osteoblastic niche signifying the quiescent state of HSCs as a protective
+
barrier during pathological conditions to fine tune the self-renewal capacity. Here [Figure 4A and B], high
level of expression in the glioma group might be due to the attempt to save the stem cell pool from the
devastating effect of the chemical carcinogen ENU. The subsequent treatment with three doses of T11TS
brings back both the HDC and LDC cells to near normal levels of Ang-1. The above mentioned effect of
Ang-1on HSCs in the glioma-bearing state is definitely mediated by over expression of Tie-2 as Ang-1 is
believed to be the dominant ligand for Tie-2 receptor in LT-BMHSCs and contributed in sustenance of stem
cell activities within the bone marrow niche . In our finding [Figure 5A and B] higher expression of Tie-2 at
[87]
LDC compared to HDC in ENU treated groups as compared to normal group hint to their protective effect
on the immature HSCs than the mature cells at HDC during ENU insult. T11TS down regulates the higher
expression of Tie-2 from both the mature and immature hematopoietic cells below normal levels, indicating
that T11TS revive the quiescent state of HSCs driving them towards normal hematopoiesis of reconstitution
and self-renewal.

In summary, our current investigation clearly demonstrated for the first time, that during glioma
condition, there was significant disruption in early phases of hematopoietic cell signaling. Our phenotypic
studies of the two compartments of HSCs comprising immature LDC and mature HDC cells indicate that
during glioma development all the receptors in both the compartments are drastically reduced due to
reversion to the quiescent state of the particular population and also cell loss due to apoptosis as hinted
in our recent publication . Their regenerative capacities were all renewed by T11TS treatment rendering
[41]
“Therapeutically equipped HSC”. Primarily the immature cells had been stimulated from the quiescent
state as shown by CD34 up-regulation. Next, they were driven towards maturity as denoted by Sca-1 up-
regulation and lastly c-kit up regulations indicating the signaling involvements towards progenitor cell
development. Up-regulation of the niche receptor Ang-1 and its counter-receptors Tie-2 of HSCs in the
glioma group and drastic down regulation of both the stem cell pool by T11TS confirms the protective
effect of T11TS to facilitate revival from the quiescent state of HSCs driving them towards differentiation
and self-renewal properties [Figure 6]. Our findings should provide helpful guidance for the therapeutic
utilization of T11TS during glioma and will also facilitate the understanding of how HSCs behave during
gliomagenic immunological shock.