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Mondal et al. Neuroimmunol Neuroinflammation 2018;5:34 I http://dx.doi.org/10.20517/2347-8659.2018.13 Page 13 of 19

Sca-1 or lymphocyte activation protein-6A (Ly-6 A/E) not only marks various developmental stages of
[71]
HSCs but also plays an indispensable regulatory role during self-renewal for normal hematopoiesis [25,72] .
[25]
In our experiment [Figure 2A and B], it has been observed that compared to the normal group, glioma
induction causes a significant decrease of the level of Sca-1 both at LDC and HDC. Evaluation with normal
counterparts, HDC population was shown to be lower than the population at LDC which might be due to
impairment of normal transition of immature HSCs from LDC to HDC during glioma growth, ultimately
resulting in a decrease in the maturity of Sca-1 HSCs due to a negative feedback effect. During T11TS
+
administration, there was a gradual increase in expressions of Sca-1 at all dose levels, both at LDC and
HDC and a sharp increase in Sca-1 cells after third dose of T11TS with higher level of expression in the
+
LDC group as pointed out in the line diagram [Figure 2]. T11TS therapy not only promotes self-renewal of
both the population of Sca-1 cells but also hints towards further maturity. Phenotypic expression of Sca-1
+
distinguishes the stem cell compartment from committed myeloid and lymphoid progenitors, as its rapid
down regulation was observed during differentiation .
[73]

The proto-oncogene c-kit, a cell surface receptor tyrosine kinase and its ligand stem cell factor (SCF)
play an essential role in intra-marrow hematopoiesis during adulthood . C-kit is exclusively expressed in
[74]
primitive HSCs to impart essential regulatory function during the early stages of hematopoiesis [75-77] . In vivo
blocking of interaction between c-kit and SCF demote HSCs self-renewal by hindering the release of HSCs
from the bone marrow. In our experiment [Figure 3A and B], ENU mediated glioma induction causes a
significant decrease of the expression level of c-kit both in the LDC and HDC as compared to the normal
group, but after treatment with T11TS, the level gradually increased with the consecutive doses (ET1 and
ET2), and the level of receptor expression is significantly higher than the glioma group and even higher
than the normal group at the third dose (ET3) both in the LDC and HDC. In glioma-bearing animals,
the lower expression level in the HDC as compared to LDC might be due to the preferential killing of
comparatively mature cells that are expressing constitutively active c-kit in terms of the active form of the
cell cycle in the HDC sparing immature more primitive dormant progenitors . Further, the comparative
[78]
line diagram [Figure 3] shows simultaneous up-regulation of c-kit cells in the HDC as compared to LDC
+
of T11TS treated groups, indicating that the primitive immature progenitors have a lower c-kit expression
as compared to their mature descendants in the HDC having higher c-kit expression. The observation
further confirms the notion that as immature primitive cells enter the phase of maturation, divide actively
and initiate the phase of differentiation, the expression of c-kit intensifies [79,80] . This is perhaps due to the
fact that the high expression pattern of c-kit opens up SCF signaling cascade to guide the HSCs towards
lineage commitment where SCF may influence the migration of hematopoietic stem cells to their ultimate
destinations of development.

Both short-term and long-term repopulating HSCs reside within the CD34 , Sca-1 and c-kit bone
+
+
+
marrow population . During normal physiological condition, a fine tune between self-renewal and
[81]
differentiation is able to maintain the constant number of HSCs. However, disease conditions such as
anemia, cancer or during myelotoxic chemotherapy have been evidence of alteration of total stem cell
number indicating that the counterbalance between self-renewal and differentiation can reconcile as
per physiological needs [82,83] . This pliability is most likely achieved by molecular crosstalk between stem
cells and their specific microenvironment called the niche. This reciprocal intracellular interaction
between HSCs and bone marrow niche also regulates the status of HSCs and influences their surface
phenotypes. On the other hand, the quiescent state of hematopoietic stem cells is thought to be critical
in sustaining a self-renewing HSC compartment for life and to shield the stem cell pool from premature
exhaustion during various pathological conditions. Indeed, the maintenance of quiescent state and slow
cell-cycle progression of HSCs could directly be linked to the robust reconstitution ability and long-
term sustainability . In addition, quiescent HSC populations are resistant to 5-fluorouracil-induced
[84]