In the bone marrow microenvironment, the mesenchymal stromal cells (MSCs) respond to the external cues and modulate the fate of hematopoietic stem cells (HSCs) via the extracellular vesicles (EVs). The EVs viz. micro-vesicles (MVs) and exosomes, therefore, form an important extrinsic mechanism through which the stromal cells regulate the fate of HSCs.

Acute myeloid leukemia (AML) is a type of blood cancer involving specific mutations that can correlate with poor prognosis in patients. In recent years, several studies have underscored the role of the bone marrow microenvironment, especially the MSCs, in the development and progression of the disease. Most of these studies have investigated the effect of the leukemic cells on the bone marrow microenvironment. However, the reverse that is how the leukemic bone marrow stromal cells (BMSCs) modulate the normal HSCs is still not clearly understood. Furthermore, so far, no study has established a correlation between the mutations in the blast cells with the signaling pathways prevailing in the BMSCs. In addition, whether such altered signaling is responsible for conferring a chemo-resistant phenotype on the leukemic stem cells (LSCs), and whether the altered BMSCs lose their HSC- supportive properties has not been investigated. This project focuses on understanding the interplay between the BMSCs and the blasts from AML and aims to decipher how the AML blasts or their extracellular vesicles (EVs) modulate the signaling mechanisms in the marrow stromal cells to their advantage. Such an understanding is crucial because one of the hallmarks of AML is over-production of the immature blasts, which crowd the bone marrow, preventing it from making normal blood cells. Such studies could provide an impetus in designing novel targeted therapies against AML that could be less toxic and more specific.

Rejuvenating effects of cord blood- / young MSC-derived extra-cellular vesicles on chemotherapy-induced damage of bone marrow mesenchymal stromal cells: in vitro and in vivo studies using an experimental AML mouse model.

To all of us, cancer is perhaps the most frightening of diseases. Acute myelogenous leukemia (AML) is a heterogeneous disease characterized by a blockade in the differentiation of hematopoietic stem cells and a clonal expansion of myeloid blasts in the bone marrow and peripheral blood. Despite several therapeutic approaches like radiotherapy, chemotherapy, etc., many patients show resistance to such therapeutic measures. In most cases, AML patients undergo relapse and succumb to the disease after chemotherapeutic measures.

Studies showed that both murine and human MSC-derived EVs were able to ameliorate radiation-induced damage to murine bone marrow cells by blocking the radiation-induced growth inhibition, DNA damage, and apoptosis.

The design of biomaterial and the supply of physical, as well as biological stimuli, play an important role in regulating cell function to create a tissue implant for clinical applications. Developing bone and cartilage biomaterials with material compositions, geometric structures, and physiological functions such as natural bone and investigating their interactions with stem cells for bone repair remain significant avenues for future research. At SCSCR we use various natural and synthetic materials, mechanical/or biological stimulation, and cutting-edge synthesis techniques to develop an engineered construct that meets the functional and biological demands of native tissue. The SCSCR team aims to discover new strategies for accelerating the repair and regeneration of lost, damaged, or diseased tissues (especially bone and cartilage) and translate these findings to help animal and human patients in need.

The goal of SCSCR is to design polymeric biomaterials for specific orthopaedic applications. At SCSCR we focus on developing synthetic and naturally-derived hydrogel biomaterials in conjunction with biochemical and mechanical stimuli to promote priming of stem cells to express a particular phenotype, as well as deliver stem cell–derived extracellular vesicles to promote healing of damaged or diseased tissues. In terms of our tissue engineering and regenerative medicine efforts, at SCSCR we primarily focus on bone and cartilage regeneration.

We are uncovering the role of mechanosensors YAP/TAZ during differentiation of human embryonic stem cells into endoderm on substrates of varied stiffness.

Adherent cells such as embryonic stem cells have mechanisms for detecting the substrate stiffness along with numerous cytokine receptors in order to proliferate or differentiate. YAP and TAZ are transcriptional regulators (part of Hippo pathway) that control genes responsible for cell proliferation, migration and cell death in response to the cell substrate stiffness. Substrate stiffness alone has been shown to regulate differentiation of mesenchymal stem cells, with stiffest substrate leads to osteogenic differentiation while lower stiffness leads to adipogenic differentiation. Stiffer substrates activate YAP/TAZ activity and has been shown to play a crucial role in maintaining undifferentiated state of human pluripotent stem cells (hPSCs). Soft substrate has been shown to induce differentiation of hPSCs into neuronal lineage. However, whether YAP/TAZ plays a role in endoderm differentiation of human embryonic stem cells is yet to be demonstrated. Currently, we are investigating the role of YAP/TAZ during endoderm differentiation of human embryonic stem cells in response to varied substrate stiffness.

Polycomb group (PcG) proteins along with other epigenetic modulators catalyse histone modifications at promoters and thus they control the expression of genes essential for lineage specification.

Human pluripotent stem cells are the cells with miraculous ability to self-renew and differentiate into all three-germ lineages and have immense potential in the fields of regenerative medicine or cell-based therapies to treat several human disease conditions. However, decades of research has shown that transforming pluripotent stem cells into a mature functional tissue is a difficult task. Thus it in order to decipher this intricate process, we have to understand the mechanism of cell differentiation and maturation. Currently we are pursuing research to understand how Polycomb group (PcG) proteins respond to differentiation cues and add inhibitory histone modifications (H3K27me3& H2AK119ub1) are promoters of crucial genes in human pluripotent stem cells. We are also investigating the role of histone deubiquitinases (H2A- DUBs) that remove the histone mark during human pluripotent stem cell differentiation into neuronal lineage.

Epithelial to mesenchymal (EMT) transition enables endometrial tissue to move to ectopic sites. We hypothesize that Polycomb group (PcG) proteins may mis-regulate the EMT genes leading to endometriosis.

Endometriosis is a condition in which functional endometrial glands and stroma grow outside of the uterine cavity and this growth leads to complications such as dysmenorrhea, dyspareunia, chronic pelvic pain, adhesions and infertility, with fibrosis routinely observed and this further contributes to pain and infertility. However, the epigenetic mechanism that leads to EMT and fibrosis in endometriosis is poorly understood. Polycomb Group (PcG) proteins are histone modifiers that can control the expression of genes involved in EMT by catalysing histone modifications; their misexpression is reported in several cancers. We hypothesise that misregulation of PcGs could lead to overexpression of EMT related genes, which may help endometrial cells migrate and cause fibrosis ectopically. To determine this, we plan to study if the PcGs protein occupy promoters and regulate EMT and fibrosis genes in ectopic endometrial cells as well when specific PcG (RING1B and EZH2) genes are repressed.

Thermal injuries can lead to hypertrophic scars, which currently do not have effective treatment. Using patient scar tissue, we are investigating whether activation of inhibition of WNT signalling can regulate ECM protein production by scar dermal fibroblasts.

Skin tissue plays multiple essential roles such as protection against invasion of microorganisms, prevention of water loss, thermoregulation and mechanosensation; and any injury to the skin tissue can disrupt these functions. Skin is a composite organ with functional co-ordination between various cell types. Trauma such as thermal burns disrupts the skin architecture and in response to the injury, cells such as fibroblasts, macrophages, platelets, and keratinocytes are mobilized to seal the damage, resulting in a scar formation. However, in many cases of severe thermal injury the scar tissue persists. This scar tissue cannot carry out thermoregulation, mechanosensation efficiently and it also restricts motion; currently, there are only few ways to reduce scarring such as pressure garments, surgery and or steroid treatment.

Prior to embryo implantation into the endometrium, there is communication via Extra Cellular vesicles (EVs). Break down in this communication may lead to failure to implantation and subsequently infertility. We are assessing the effect of placental EVs on the signalosome in endometrial cells derived infertile women.

The fetal trophoblasts cells secrete EVs than help embryo implantation and later the syncytiotrophoblasts regulate the maternal immune response and help complete pregnancy to term. Moreover, in the cases of infertility, the lack of communication between the fetal and maternal cells could be the reason for preterm delivery or spontaneous abortion or recurrent miscarriages.