Hematopoietic stem cells niche and its control Adult stem cell plasticity and epigenetic modifications (Hepatic cells and dopaminergic neurons) Cellular therapy: Parkinson’s disease, liver fibrosis and hemophilia A Hematopoietic cells in progression of cancer Bone tissue engineering
Summary of Research:
Hematopoietic stem cells (HSCs) niche plays an important role in deciding on the engraftment and fate of the exogenous stem cells. Our study has shown that during marrow regeneration, the donor HSCs are transiently amplified following symmetric division of cells. Further studies have demonstrated that donor hematopoietic cells rescue host HSCs from apoptosis and also induce proliferation by activating cell cycle regulators. Transient amplification of donor HSCs during bone marrow (BM) regeneration, followed by entry into quiescent stage suggests that hematopoiesis is a dynamically controlled process, in which niche and the stromal cells have major role. In cDNA microarray and real-time RT-PCR analyses, we have observed that the robust expressions of different hematopoietic growth factor genes are restricted to the very early stage of marrow regeneration. Besides these known growth factor genes, many unknown genes are also highly expressed, the physiological significance of these gene products are unknown with respect to hematopoiesis. At present we are involved to decipher these genes for their functional relevance. Another interesting area of hematopoietic system in which we have been working is aging of stem cells. Preliminary results suggest that aging of HSCs is not only related to the intrinsic factors of the cells, some extrinsic factors do have significant influence on aging.
Shortage of donor organs/tissues and their timely availability are two major global problems in transplantation medicine. For the past many years our laboratory is working on adult stem cell plasticity, so that the cell therapy process can be translated in some of the human degenerative and genetic diseases without much complicacy. In liver we are studying in the phenotypic conversion of hemophilia A and a-antitrypsin-1 deficient mice by cell therapy. We are also working in liver fibrosis with the intension of developing BM cell therapy for the treatment of fibrotic liver of pre-cirrhotic stage. In the whole liver regeneration programme, we are following two different approaches (a) in situ direct differentiation of BM-derived stem cells into hepatocytes, and (b) induced-hepatocytes by over-expressing master regulator gene in the fibroblast cells. By real-time PCR and FISH analyses we have shown that in regenerating liver, BM-derived cells can engraft and directly differentiate into hepatocytes and endothelial cells. We have also shown phenotype correction in hemophilia A mouse by transplantation of uncommitted BM cells. The donor-derived cells are found to express active factor VIII protein for long duration without forming any inhibitors. We have started investigating genetic and epigenetic changes in the BM-derived hepatic cells to address the mechanism of lineage switch. In cell/organ transplantation, immune rejection is the central issue for failure of treatment. We have found that the rejection of allogenic cells in liver can be averted by inducing peripheral tolerance, when co-transplanted with allo-reactive Treg cells.
In another project related to plasticity research, we observed that fetal liver-derived mesenchymal stem cells (MSCs) are capable of differentiating into neuronal cells, which are found to be comparable to the dopamine expressing neurons. These cells, upon transplantation, show improvement in the behavioural responses in Parkinson’s disease (PD) mouse model. The cellular and molecular mechanism of differentiation of MSCs into dopaminergic neurons are currently under investigation.
This laboratory is also interested to understand the role of hematopoietic cells in metastasis and progress of tumour. We are working on two different tumour models: ovarian and lung. It has been found that in both types of tumours, a specific subtype of hematopoietic lineage of cells is predominantly fused with tumour cells. The fused cells are found to have greater migration ability and lesser genetic stability than the normal tumour cells. We believe that fusion of cells lead to gain of certain functional properties by the tumour cells through the contribution of active molecules of hematopoietic cells.
Dr Prakash Baligad (RA), Mallika R (PhD student), Amit K Jaiswal (PhD student), Abinaya Sundari T (PhD student), Veena K (PhD student), Sushmita Roy (SRF), Neety Sahu (JRF), Saborni Chattopadhyay (JRF)