In this issue: New research with induced pluripotent stem cells is shedding new light on our understanding of SDS!
Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email genetics@SDSAlliance.org or message us on Facebook! This is all for you!
Unlocking the Secrets of Early Development in SDS with Induced Pluripotent Stem Cells
Shwachman-Diamond syndrome (SDS) is a rare genetic disorder that affects the bone marrow, leading to a shortage of blood cells. It can also cause other problems in the body and increase the risk of leukemia, a type of cancer. The disorder is mainly caused by mutations in the SBDS gene, which is important for making ribosomes, the cell’s protein factories. Without proper SBDS function, not enough ribosomes can form, leading to many of the issues seen in SDS.
In the SDS & Science Snapshot this week, we are highlighting a recent study led and published by Dr. Yigal Dror, a leading physician-researcher on inherited bone marrow failure syndromes from The Hospital for Sick Children (SickKids in Toronto). In this study, Dr. Dror and his research team wanted to find out exactly when the blood cell problems of individuals with SDS begin during development with the hopes of guiding future research in therapy development.
To do this, Dr. Dror and his research team created a special type of cell called induced pluripotent stem cells (iPSCs) using cells from bone marrow samples from SDS patients and healthy controls, which can turn into any cell type in the body. This ability to “shape shift” makes iPSCs a powerful tool for studying early embryonic development, as they can be used to observe how diseases or genetic conditions affect the formation of different cell types from the very beginning. Additionally, iPSCs can be used to model diseases in the lab, allowing scientists to explore new treatments and understand the underlying mechanisms of various disorders without the need for embryonic stem cells. For more information about the important use of iPSCs in research, you can watch the video below.
Key Findings from this Study:
Lower Efficiency in Cell Reprogramming: The researchers found that it was much harder to create iPSCs from SDS patients compared to heathy donors, suggesting that cells from SDS patients are either less fit or have a reduced ability to be reprogrammed into stem cells.
Defects in Blood Cell Formation: When the iPSCs from SDS patients were encouraged to become blood cells, they formed far fewer blood cells than the healthy iPSCs. This means that the blood cells in SDS patients have trouble developing properly, which can explain the issues with healthy blood cell development (like neutropenia) seen in SDS patients.
Early Developmental Issues: The study also showed that the problems start at a specific stage of blood cell development, known as the early emerging hematopoietic progenitors (EHPs) stage. This is an early step in the process where stem cells start to become specialized blood cells. SDS cells had fewer EHPs, and these cells were less able to grow and multiply.
Potential for New Treatments: One exciting aspect of this study is that the researchers found that adding back the SBDS gene to the SDS iPSCs improved their ability to form blood cells. This suggests that gene therapy, which aims to correct the defective gene, might be a promising treatment for SDS. Additionally, understanding the specific stages and processes affected by SDS helps in designing drugs that can target these problems more precisely, and provides a rationale to apply treatments as early in life as possible.
Mapping Gene Pathways in SDS: Lastly, the researchers in this study investigated the gene expression during early development of these iPSCs from SDS patients. By analyzing these iPSCs, they identified important genes and cellular pathways that are activated or repressed at various stages of cell development. This detailed mapping of gene activity may help in understanding the differences between healthy and SDS iPSCs, providing valuable information for developing targeted therapies for SDS.
Understanding exactly when and how blood cell problems start in those with SDS can help scientists develop better, more effective treatments. By knowing that the defect begins at the EHP stage, researchers can target this stage to find ways to prevent or correct these defects. These findings could help lay the groundwork for new therapies that can improve blood cell production in SDS patients, reducing the need for frequent treatments and improving quality of life. This also underscores the critical importance of early and accurate diagnosis of SDS, so that any treatment can be started as early in life as possible, when the benefits may be the biggest. With continued research, there is potential for significant improvements in managing and treating SDS!
Lagos-Monzon A, Ng S, Luca AM, Li H, Sabanayagam M, Benicio M, Moshiri H, Armstrong R, Tailor C, Kennedy M, Grunebaum E, Keller G, Dror Y.
Aberrant early hematopoietic progenitor formation marks the onset of hematopoietic defects in Shwachman-Diamond syndrome. Eur J Haematol. 2024 Jul 5. PMID: 38967591.
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