Hematopoietic stem cells are progenitor premature cells that proliferate into different type of blood cells in our body. They are usually found in the bone marrow as well as umbilical cord. Till the birth of the child, hematopoiesis is done by liver and spleen of the child.
After the child birth, bone marrow does the hematopoiesis process. The liver and spleen might get involved in the creation of new blood cells after the birth when in the case of any infection. Hematopoietic stem cells form two main progenitor cells from which the main cells circulating in blood descend. Common lymphoid progenitor cells differentiate into four different lymphoblasts with different genetic profiles. These lymphoblasts in turn form Naive B-cells, Pre-T-cells, Natural Killer (NK) cells and premature Dendritic cells. They get transferred into the blood from bone marrow for maturation.
Common myeloid progenitor cells form promonocytes that circulate in blood and mature to form macrophages, mast cell precursors that form mast cells in blood, myeloblasts that differentiate into granulocytes(basophils, eosinophils and neutrophils), megakaryocytes that form platelets in blood and, erythroblasts which lose their nuclei to form RBCs in blood.These hematopoietic stem cells are taken into consideration for treating many forms of cancer, especially leukaemia and multiple myeloma. Many papers and works have been put forward to come with an approach of using these multipotent cells to treat cancer. One such oncologist and Investigator at Harvard Medical Institute, Leonard I.Zon has compaired the hematopoietic development in zebrafish and humans.
He has come up with many discoveries and many solutions to treat leukemias, lymphomas and myelomas. He chose zebrafish for his study mainly because of three specific reasons: (i) it lays many embryos a week; (ii)it has the potential to develop blood cells within one day, and, (iii)these blood cells can be easily visualized under microscope to see them develop and differentiate. He found that prostaglandins increase the production of blood stem cells and these lipids have the capability to enhance the engraftment(successful transplantation) of hematopoietic stem cells upon bone marrow transplant. This gave rise to a question like how can prostaglandins and other parameters can boost up the HSC production. He has also studied the new transgenic lines in zebrafish by dissecting their hematopoietic development. This then gave him a way to use the novel transgenic lines to see the HSC transplant in a model. He created first animal model (zebrafish-melanoma model) to come across an epigentic upregulator called, SETDB1, that is produced in high amounts in a few human melanomas.
Apparently, this regulator motors the effects of melanoma during the initial stages in the zebrafish. This was an evidence to identify the genetic and epigentic regulators that are involved in melanoma onset as well as the steps of hematopoiesis. HSC transplant is still prevalent in treating cancers. It deals with the grafting of autologous or allogenic stem cells to anew the hematopoietic abilities in a patient whose immune system is damaged. Autologous transplantation involves the usage of own stem cells and allogenic transplantation requires a donor to be the source of stem cells. In case of allogenic transplantation, stem cells are surgically taken out of the donor’s bone marrow (usually pelvic bone) under general anesthesia. Blood is drawn out from the bone and is frozen and stored for subsequent purposes. In autologous transplantation, the blood stem cells are extracted from the patient itself.
In this case instead of pelvic bone, active rhesus process is used which involves peripheral blood stem cells. In active rhesus, blood is drawn from the patient’s arm and the blood is separated into blood cells and stem cells by a machine. The regular blood cells are then transferred back into the patient through IV.
The recipient is firstly subjected to high chemotherapy to kill all the good and tumour cells. The stem cells are then transfused intravenously to create a new and healthy cells. Mostly autologous transplantation is taken into consideration as many complications arise in case allogenic transplantation. These complications include immune system getting repressed and the graft-versus host disease in which new cells fail to recognize the host cells and start to attack the body cells. Even sometimes autologous transplantation can have complications such as infection which might be proven fatal considering the fact that the immune system is already weak. Even though the cons are high, the pros like they replace damaged cells, help in fighting cancer have turned out to have overweighed the limitations.
Three researchers, Eric, Satiro de Oliviera and Donald, have submitted a paper on cancer immunotherapy by hematopoietic stem cells. Their paper includes the provision of active targets for the treatment of cancer by the introduction of genes encoding T-cell receptors or chimeric antigen receptors(CARs) that are against the tumour antigens. Autologous HSCs are designed with pre arranged anti cancer antigen TCR or CAR. The effects of these engineered cells are twofold, one the production of anti cancer effector cells and two, preventing the TCR mispairing i.e. the coexpression of already present TCR could mis-pair with the new introduced TCR chains.
Through ex vivo gene transfer, HSCs can be enhanced by immune selectivity method with the help of monoclonal antibody to the surface antigen called CD34. Vectors which have originated from Retroviridae family are used for permanent gene insertion in HSC chromosomes. Another approach of gene transduction of HSCs is used where CD34+ T cells are enriched in a medium that has recombinant human cytokines and thrombopoietin that can activate the HSCs from dormant state for 1-2 days and then they are subjected to vector.
These prepared cells are then used for intravenous transfusion later on. This insertion of a new transgenes improves the HSC engraftment and multi potent blood cell production. The expression of this transgene is done by the transcriptional control element such as viral enhancer or promoter in a whole lineage of blood cells. But this also depends on other factors. For example, if CD3 compliment proteins need to be expressed, then transgenic TCR products won’t be expressed even if the vector is present. In such cases, vectors are formed to make them make use of lineage specific transcriptional regulators to inhibit the expression to specific cell forms. The self renewing nature of HSCs will help in the provision of effector T cells directed against specific antigens.
The CAR modified HSC will enhance the “memory’ power of immune system by producing T-lymphocyte progenitors. CAR modified HSCs can also help in the increased production of NK cells and myeloid cells along with T cells that express the CAR protein widening the horizon of targeting tumour cells.