MicroRNA target homeobox messenger RNA in HIV induced hematopoietic inhibition.

Cytopenias are a common occurrence due to abnormal hematopoiesis persistent in patients suffering from and advancing with HIV/AIDS. In order to develop efficacious therapies against cytopenias, it is necessary to understand the mechanisms by which HIV infection affects the differentiation of hematopoietic stem-progenitor cells (HSPCs), causing hematopoietic inhibition, that leads to hematological disorders. Currently, only the antiretrovirals that are being used to treat HIV infection and indirectly lower the levels of virus replication also co-attenuate cytopenias. The evidence available suggests that this indirect efficacy may not prevail for the lifetime of the infected patients, and the acquired immunodeficiency can overtake the beneficial consequences of decreased virus replication. As cited in this article, we and our colleagues are the first to make a foray into the involvement of microRNAs and their use as potential interventional treatments for the cytopenias that occur with HIV/AIDS. Herein, we progressed further in the direction of the mechanisms of the involvement of homeobox gene regulation to cause cytopenias. We had previously shown that HIV-1 inhibits multi-lineage hematopoiesis of the CD34+ cells using SCID-hu Thy/Liv animals in vivo. Furthermore, we demonstrated that the virus-induced hematopoietic inhibition occurred despite the CD34+ cells being resistant to HIV-1 infection. We set out to search for the specific host factors secreted by CD4+ T-cells that likely participate in the inhibition of hematopoiesis of the HIV infection-resistant CD34+ cells. More recently, we reported the identification of virus-infected CD4+ thymocyte-secreted miRNA-15a and miRNA-24 and that their differential expression following HIV infection causes the indirect inhibition of hematopoiesis. We then hypothesized that the observed miRNA differential expression in the virus-infected T-cells causes the abnormal regulation of homeobox (HOX) gene-encoded transcriptomes in the CD34+ cells, affecting specific MAPK signaling and CD34+ cell fate, thereby disrupting normal hematopoiesis. We present that in HIV infection, miRNA-mediated post-transcriptional dysregulation of HOXB3 mRNA inhibits multi-lineage hematopoiesis, which translates into hematological disorders in virus-infected patients with HIV/AIDS. These observations portend specific microRNA candidates for potential efficacy against the virus-induced cytopenias that are otherwise not treatable by the existing HAART/ART regimens, which are primarily designed and applicable for the attenuation of virus replication.

Contrasting mechanistic susceptibilities of hematopoietic and endothelial stem-progenitor cells in respective pathogeneses of HIV-1 and SARS-CoV-2 infections.

The multitude of cellular types can be expected to behave differently when receiving invading pathogens such as mammalian viruses. The nature-dictated causes for such intrinsic cellular diversity become the criteria for the emergence of specific virus-receptor interactions on that particular host cellular surface, in order to accommodate contact with various other living entities whether desirable to the host or not. At present, we are presented with an example of two contrasting behaviours wherein the well-known HIV-1 and the more recently emergent SARS-CoV-2 cause adverse consequences to the differentiation and functions of progenitor stem cells. These include the two different downstream multipotent CD34+ hematopoietic (HSPC) and CD133+ endothelial (ESPC) stem-progenitor cells of their common pluripotent hemangioblast precursors. The two viruses target the respective endothelial and hematopoietic stem-progenitor cells to thrive upon the relevant host cellular surrounded stromal microenvironments by adopting reciprocally-driven mechanistic routes, which incidentally cause pathogenesis either directly of ESPC (SARS-CoV-2), or indirectly of HSPC (HIV-1). HIV-1 utilizes the CD4+ T-lymphocyte receptor thereby advancing pathogenesis indirectly to the CD34+ HSPC. SARS-CoV-2 directly targets the CD133+ ESPC via ACE2 receptor causing cytokine storms of the CD4+ T-lymphocytes. In this manner, these two viruses cause and extend their damage to the other cellular sub/types coexisting in the host cellular microenvironments. The infected individuals require clinical interventions that are efficacious to prevent cellular dysfunction and ultimate cell depletion or death. We infer from these viruses mediated pathogeneses mechanisms a potential common origin of microRNA molecular therapies to address cellular dysfunctions and prevent cell loss.

Ligament and tendon repair through regeneration using mesenchymal stem cells.

One of Nature's gifts to mankind is mesenchymal stem cells (MSC's). They are multipotent in nature and are present literally in every tissue. Since, they possess certain characteristics of stem cells such as self-renewal and differentiation they are known to be one of the key players in normal tissue homeostasis. This novel function of mesenchymal stem cells has been explored by scientists in the field of regenerative medicine. This review gives an insight of the various sources of mesenchymal stem cells available for tissue engineering with regard to tendon and ligament and the mechanism involved during regeneration.

Hematological malignancies: disease pathophysiology of leukemic stem cells.

Hematopoietic homeostasis is maintained throughout the lifetime of an individual through self-renewal of hematopoietic stem cells. Defects in the self - renewal and differentiation lead to hematopoietic insufficiency and development of malignancies. Leukemic stem cells (LSCs), which are considered to originate from hematopoietic stem or progenitor cells, not only adopt the regulatory machinery operating in normal HSCs but establish their own mechanisms against apoptosis and senescence. Hematopoietic malignancies are of Lymphoid origin with CLL and ALL and myeloid malignancies with AML and CML and in addition there are disease of the plasma multiple myelomas. One of the major therapeutic strategies for hematological malignancies is hematopoietic stem cell transplantation along with combination of chemotherapy. The review gives an insight of different hematological malignancies, the mechanism and therapeutic strategies available at present.

Functional role of solid tumor stem cells in disease etiology and susceptibility to therapeutic interventions.

Cancer stem cells (CSCs) are defined by their innate stem cell like properties and can be identified by specific markers that include antigens, molecules and signaling pathways. Like stem cells, CSC divide indefinitely giving rise to both more CSCs and differentiated cell progeny. CSCs can give rise to tumors that phenotypically resemble their origin, either morphologically or by expression of tissue specific genes. Tumors arise from a single cell, the CSC, but the cells that constitute the tumor are not identical to each other. Evidence of heterogeneous populations within a tumor has led to an investigation of the cellular hierarchy of cancers. This review gives an overview of cancer stem cells, from breast, cervical, lung, prostate, head and neck, glioblastoma, pancreatic and colorectal cancers and mechanisms implicated in tumor development and therapeutic interventions.

Cancer-initiating cells as target for prevention of recurring disease etiology: role of these malignant putative progenitor cells in relapse or metastasis of human cervical carcinoma.

Evidence suggests that there is a link between high-risk human papillomaviruses (HPVs) and cervical cancer. Studies indicate that persistence of high risk HPVs may determine progression to more severe stages of cervical disease, while the majority of HPV infections are transient and do not seem to be important in cervical carcinogenesis. Earlier studies in different cancers have shown that tumor initiating cells TICs are responsible for tumor formation and progression and interestingly, they are endowed with stem/ progenitor cell properties. In particular, TICs share with stem cells the key feature of self-renewal. The most efficacious therapeutic intervention for cervical cancer is probably vaccination. This review gives an overview on cervical cancer and its potential therapeutic interventions.

Coexpression of Notch1 and NF-kappaB signaling pathway components in human cervical cancer progression.

OBJECTIVES: Features of deregulated Notch1 signaling and NF-kappaB activation have independently been reported in cervical cancers. Here, we have extended these observations and examined both these pathways simultaneously in human cervical cancer tissue. Further, we have investigated the potential cross-talk between these pathways in a human cervical cancer derived cell line CaSki, which mirrors features of Notch activation as in the majority of human cervical cancers. METHODS: Cervical tissue samples were analyzed for the expression of Notch1, Jagged 1, Hes1, pAKT, NF-kappaB p50, NF-kappaB p65, IkappaB-alpha, Bcl-2, CyclinD1, Cdk9, c-Fos, and p53 by immunohistochemistry. A total of 352 samples were analyzed which included 69 normal cervical tissue, 132 preinvasive lesions and 151 squamous cell carcinomas of the uterine cervix. Dual immunofluorescent analysis was performed to evaluate the coexpression of Notch1 and NF-kappaB. Transcriptional reporter assays and xenografts were undertaken with CaSki cells. RESULTS: Features of Notch1 activation as measured by intracellular Notch1, high levels of Jagged1, Hes1 and Cdk9 were paralleled by nuclear translocation of both NF-kappaB p50 and p65 with target gene expression (IkappaB-alpha, Bcl-2, and CyclinD1) in human cervical cancer sections. Reporter assays in CaSki cells are consistent with Notch being an upstream regulator of NF-kappaB. Further, the xenografts recreate key aspects of human cancer tissue. CONCLUSIONS: Results from this study suggest that there is a co-activation of Notch1 and NF-kappaB signaling pathways at the cellular level in the majority of human cervical cancers, with Notch as an upstream regulator.