Scientists stumbled upon hematopoietic stem cells (HSC) during World War II while treating patients whose blood cells were destroyed by high levels of radiation. They found that transplanting the spleen and bone marrow of healthy subjects produced new blood cells in these patients. Further research showed that the cells involved in this recovery are HSCs, which are multipotent stem cells — these cells have the capacity to differentiate into multiple blood cell types; erythrocytes, eosinophils, basophils, megakaryocytes, platelets, T cells, B cells etc. Following this, the process of formation of new blood cells called hematopoiesis became a subject of intense study.
The drosophila larval model system lends itself to studying the cellular, molecular and genetic mechanisms behind hematopoiesis. It was found that larval hematopoiesis followed similar trajectory as mammalian systems, with homologous genes and molecular mechanisms. However, there was one huge lacuna — HSCs were never actually found in drosophila—until recent work by Lolitika Mandal and her group from Indian Institute of Science, Education and Research in Mohali.
One of the sites of hematopoiesis in the drosophila larva occurs in the lymph gland, a multi-lobed organ straddling the dorsal vessel, the rudimentary embryonic heart. The primary lobe of the lymph gland has a central region of densely packed cells called the medullary zone (MZ) and a surrounding zone with loosely packed cells called cortical zone (CZ). Posterior to both is a small group of cells called the posterior signaling center (PSC) which regulates the hematopoietic process. The MZ cells houses the progenitor cells and differentiated blood cells are found in the CZ.
Previous studies in drosophila larva have shown that progenitor blood cells express a marker gene, domeless, in the later developmental stages. In this study, the scientists looked for stem cells in an earlier developmental stage, hunting for cells that could have given rise to the progenitor cells. They found a unique group of cells expressing the marker genes of stem cells (Notch) and not expressing the marker for progenitor, domeless in the medullary zone of the lymph gland close to the dorsal vessel. These cells were also found to express other genes associated with stem cells implying the presence of a previously unidentified group of cells in early larval lymph gland. Increasing the expression of these suspected HSCs, they found that these cells were unique in size, count and in the expression of stem cell molecular markers.
The defining characteristic of stem cells is their multipotency, which was confirmed by lineage tracking experiments, which showed that HSCs gave rise to most of the cell types in the third instar larval lymph gland. They also confirmed that the HSCs had all the features of stem cells; slow proliferation, asymmetric differentiation and a unique molecular signature reflecting its stem cell properties.
Differentiation of stem cells into different lineage depends on the micro environment and the homeostasis is intricately maintained by many genes and molecules. The researchers investigated the signals that are required to maintain these transient HSCs. They found that Dpp, a gene implicated in many aspects of stem cell homeostasis was involved in the maintenance of HSCs and their ablation caused a reduction of lymph gland size and number of the progenitor cells.
“This study has some far-reaching implications including stem cell based therapies. We were lacking an amenable vertebrate model to analyse the early events related to HSCs. Now, our fly model can unravel the mechanisms relevant for normal development as well as pathological events related with embryonic HSC” says Lolitika Mandal.