Topic:
Single Cell Omics and Machine Learning in the Determination of Hematopoietic Stem Cell Signature
Presenter:
Dr. Ahmad Waraky – Visiting Researcher at Cambridge Stem Cell Institute
Date and Time:
Friday, Dec 15, 2023 at 2:00 PM
Location of event:
Debbieh Campus, Meeting Room A3 Building
Zoom:
https://zoom.us/j/96417417775?pwd=bEd3WmFsNlZyWGh2WXpBTVd6MUhDZz09
Biography:
Dr. Ahmed Waraky is currently a Postdoctoral Research Fellow at the Cambridge Stem Cell Institute (Cambridge University, UK), holding affiliations with the Department of Clinical Chemistry at Sahlgrenska University (Sweden). His academic journey commenced at the Karolinska Institute in Sweden, where he successfully obtained his Ph.D. in Molecular Biology and Cancer Drug Discovery under the guidance of Prof. Olle Larsson and Prof. Eiman Aleem. Transitioning into bioinformatics and epigenetics, he was awarded the Children's Cancer Fellowship, conducting postdoctoral research at Prof. Elisa Laurenti's lab in Cambridge University, UK, and Prof. Lars Palmqvist's lab at Sahlgrenska University Hospital, Sweden. Dr. Waraky'scurrent research is centered at the intersection of machine learning and single-cell omics in hematology. As a co-founder of the biotech startup K-Stem, he directs efforts toward leveraging AI for the advancement of stem cell transplantation. With a string of ten publications, including a recent feature in Hematologica, and active collaborations within the hematology field, including membership on the publication committee of the International Society of Experimental Hematology, Dr. Waraky's work aims on unraveling the biological complexities of developmental and hematological malignancies through the lens of computational biology.
Abstract:
Hematopoietic stem and progenitor cells (HSPCs) are vital for the ongoing replenishment of all blood cells via the process of hematopoiesis. Recent studies using single-cell technologies have shown the hematopoietic stem cells (HSCs) and HSPC compartments to be more heterogeneous than expected. HSC populations with similar cell surface markers appear to be comprised of different subpopulations that are very heterogenous on the transcriptional level. Moreover, HSCs from the medullary bone marrow (BM) compartment were shown to be different both on the transcription and on the functional level from the extramedullary HSCs. Furthermore, even transcriptionally homogeneous HSCs/MPPs display variations in chromatin accessibility and lineage-specific transcription factor (TF) activity at the chromatin level. These heterogeneity of HSPCs are of particular importance in hematological malignancies where both leukaemia-initiating and relapse-initiating cells appear to inhabit the phenotypic HSPC compartment with same cell surface markers, but with differences on the transcriptome and/or epigenome single cell level. In the current study, we aim to determine the stemness signature of hematopoietic stem cells in various contexts and comprehend the influence of epigenetic priming on shaping or modifying the molecular states of hematopoietic stem cells in both physiological and malignant conditions. These studies we hope will open the way for novel clinical diagnostic strategies, potential combined therapies for enhancing HSC transplantation, and the identification of markers for measurable residual diseases (MRD). Additionally, these findings could provide insights into the hierarchical organization of leukemia stem cell populations in different AML subtypes, enabling the development of tailored treatments for these resistant cell populations.
Using scATAC-Seq analyses integrated with scRNAseq and scCITE-Seq we were able to further characterize long-term hematopoietic stem cells (LT-HSCs) and identify different LT-HSC subpopulations, based on previously characterized unique chromatin peak signatures, scCITE-Seq and scRNAseq. The abundance of these subpopulations differed between the medullary and extramedullary compartments, with erythroid and myeloid primed subpopulations almost exclusively in the BM and lymphoid primed subpopulations in the spleen, in addition to a non-lineage primed subpopulation which was present in both BM and spleen. Each subpopulation showed divergent chromatin motifs and chromatin accessibility patterns, with the unique non-lineage primed subpopulation showing the lowest chromatin accessibility, highest enrichment for CTCF motifs and lowest enrichment for transcription factor motifs involved in cell cycle and mRNA transcription including the AP-1 complex JUN and FOS, suggesting a high quiescence status. The role of CTCF motif enrichment in chromatin accessibility and quiescence, as well as its involvement in hematological malignancies, is still under investigation.
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