With few exceptions, proper functioning of early hematopoietic stem and progenitor cells are dependent on c-kit, stem cell antigen-1 (Sca-1) and CD34 mediated signalling system for their self-renewal, proliferation, and survival. HSCs are delineated by their propensity for self-renewal and differentiation into entire committed hematopoietic lineages. There has been little success in preventing destructive nature of glioma either by modulating glioma stem cells or by using genetically engineered stem cells in glioma therapy. However, there is an iota of literature about the status of bone marrow-derived HSCs during glioma condition and/or immunotherapeutic modulation of HSCs. Viewing HSCs as the foundation for the immune response we hypothesize that global immune suppression during glioma progression might have an important deleterious bearing on synchronized internal signaling network of hematopoietic machinery that regulates HSCs homeostasis, proliferation, and migration. The immunosuppressive, IL-10 is found to contribute its inhibitory impact in hematolymphopoiesis during various pathological conditions. PGE2 regulates hematopoiesis in a dose and time-dependent manner and modulates hematopoiesis as negative and positive feedback control. Malignant brain tumor derived gangliosides inhibited hematopoiesis at different stages of differentiation and resulted in bone marrow hypoplasia. TGF-β, a key negative regulator of hematopoiesis not only suppresses in vitro proliferation of both progenitors and mature stem cells but also induces quiescent state of functional hematopoietic stem cells (HSCs). Interestingly, gliomagenic generation of potent immune suppressors in addition acts as intense inhibitory regulators of hematopoiesis by modulating the function of bone marrow hematopoietic stem cells (BMHSCs). Debilitating gliomas evade the host immune surveillance either by adopting immune-editing strategies such as impairment of antigen presenting machinery, activation of negative co-stimulator signals for example cytotoxic T-lymphocyte-associated protein 4 (CTLA4), B7 homolog 1/programmed death 1 (PD1) and Programmed death-ligand 1 (PDL1) and recruitment of pro-apoptotic pathway, expansion of regulatory T cell population and down regulation or absence of tumor specific antigen or by secreting cytokines such as interleukin 10 (IL-10), interleukin 6 (IL-6), transforming growth factor beta 1 (TGF-β), prostaglandin E2 (PGE2), and various gangliosides which have been implicated for their direct immune suppressive role to diminish the antitumor immune response during glioma progression. Systemic depression of cellular immunity and subsequent global immune suppression is the classical poor prognostic fact of gliomagenesis. The results flowcytometric-analysis was also well corroborated with immunofluorescence imaging and western blot analysis.Ĭonclusion: Collectively, the above experimental evidence hints towards gliomagenic maneuver of receptor expression of HSCs to derange the systemic immunity and T11TS mediated manipulation towards revival/rejuvenation of the same. T11TS administration reversed the gliomagenic transformation of expression of the above mentioned markers.
Results: There was significant downregulation of HSCs-markers CD34 +, Sca-1 +, c-kit + in ethyl nitrosourea-induced glioma-bearing animals followed by an increase in the expression level of Ang-1 and Tie-2 that determines the quiescence and self-renewability of stem cells. Immunofluresenece imaging and western blot analyses of BMHSCs were also carried out. Methods: Flowcytometric analysis of cultured BMHSCs was evaluated for assesing the expression pattern of early hematopoietic stem cells (HSCs) markers such as CD34 +, Sca-1 +, c-kit + and also Angiopoietin-1 and Tie-2 both in normal, glioma, and in T11TS treated glioma-bearing animals. Therefore, we aimed to delineate the effects of T11TS on immature and mature compartments of hematopoietic machinery. The status of bone marrow hematopoietic stem cells (BMHSCs), the cradle of regeneration of all blood cells, during gliomagenic global immune devastations has not yet been investigated.
Aim: T11TS, a potent anti-gliomagenic glycoprotein, stimulates both peripheral and intracranial immune response.
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