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Shedding new light on intermediate cell states as stem cells decide their fate

Team of researchers behind the findings. Group Photo.
The members of the Stem Cell and Leukaemia Research Group.

Researchers at Lund University have recently sought to shed more light on how normal hematopoietic stem cells (HSCs) produce a vast variety of blood cells. Their latest findings, now out in Cell Reports this week, confirm the existence of a transition state as HSCs develop into functional blood cells and provide insights into how certain properties of HSCs are lost as these cells decide their fate.

Hematopoiesis, the production of new blood cells, is a process that takes place in our bodies daily, generating billions upon billions of blood cells from a small pool of hematopoietic stem cells (HSCs). These stem cells are multipotent and can differentiate or develop into all lineages or types of blood cells, including white blood cells, red blood cells, and platelets. At the same time, they are also capable of long term self-renewal, meaning that they can also develop into new blood stem cells.

At Lund University, the research group on Stem Cells and Leukemia, led by Dr. Göran Karlsson, is interested in better understanding HSCs on a molecular level to distinguish between normal and malignant stem cells and explain the molecular basis for leukemogenesis - the generation of blood cancer cells.

“Our research focuses on both normal and leukemic stem cell biology with our latest project, focusing on how normal stem cells perform the first differentiation step into different lineages using single-cell genomic analyses,” explained Göran.

The group’s latest study reveals a unique transition state as HSCs develop into blood cells, demonstrating how the properties of self-renewal and multipotency are lost as these cells decide what type of blood cell to become.

Graphical Abstract. Image Credit: Christine Karlsson.
Graphical abstract from the study. Image Credit: Christine Karlsson.

"What our findings indicate is that these transitional cell states do exist, and they can be found using the approaches employed in our study.  These approaches allowed us to capture these elusive cell states and understand how stem cells make cell-fate decisions in early stages of differentiation, which is in sharp contrast to the current school of thought based on single-cell RNA-sequencing," highlighted Fatemeh Safi, Ph.D. student and lead author of the paper.

As these transitional states are rare, there has been some debate regarding their existence. Although the field has relied heavily on sensitive and sophisticated analyses, current approaches have largely been unable to demonstrate a cell stage which displays features of more than one lineage downstream of HSCs.

"The early steps of differentiation are mired in controversy as their presence is typically undetectable using single-cell RNA-sequencing based approaches. So, we suggested that perhaps we could solve this problem by using alternative approaches, such as, single-cell chromatin accessibility analysis (scATAC-seq) and enriching transitional states by using cell surface markers,"said Ram Krishna Thakur, post-doctoral researcher and co-author.

To do this required several layers of state-of-the-art analyses and the development of new analysis tools. "In total, a suite of 10 computational, in vitro, and in vivo assays, were done on a small population of cells. This has led to robustness in our findings, but more importantly, it is also something which could potentially impact how we approach and analyze this type of data in the future," noted Parashar Dhapola, Ph.D. student, and co-author.

By using these approaches, the team was able to dive into the functional and molecular aspects of the early stages of hematopoiesis. Utilizing their expertise in basic stem cell biology, they determined a combination of surface markers to help enrich the stages of differentiation, allowing them to detect the transitional states along with their molecular features.

"We were able to identify cells that sit between stem cells and differentiated blood cells. These intermediate or transitional cells have features which somewhat resemble stem cells in terms of multipotency, but also display features of lineage-specific programs," revealed Ram and Göran.

This discovery provides a new way of looking at cell fate and the differentiation process - adding new knowledge and new methods of analysis to the knowledge base and serving as building blocks on which future research can be based. The group already has several experiments underway in the laboratory where they plan to study similar cell populations both in human samples and experimental models in aging and leukemia.

"While this research is very basic in its nature, the knowledge gained on how a cell decides to differentiate can impact our understanding of leukemia, as many leukemic cells fail to differentiate. Additional research is needed going forward, but these transitional cells will be interesting to study further as they can possibly help in better understanding the origin of leukemia,"concluded Göran and Ram.


This study was conducted in collaboration with principal investigators of three research groups based at the Lund Stem Cell Center including Dr. David Bryder, Dr. Ewa Sitnicka, and Dr. Charlotta Böiers. It was also supported by grants from the Swedish Cancer Society (Cancerfonden), the Ragnar Söderberg Foundation, the Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Swedish Society for Medical Research, and the Swedish Childhood Cancer Foundation (Barncancerfonden).

Contacts:

Göran Karlsson

Principal Investigator
PhD, Associate Professor
Division of Molecular Hematology

Phone: + 46 46 222 12 61
Mail: Goran [dot] Karlsson [at] med [dot] lu [dot] se


Ram Krishna Thakur

Postdoctoral Researcher, PhD
Division of Molecular Hematology

Email: ram_krishna [dot] thakur [at] med [dot] lu [dot] se


Fatemeh Safi

Ph.D. Student
Division of Molecular Hematology

Email: Fatemeh [dot] safi [at] med [dot] lu [dot] se


Parashar Dhapola

Ph.D. Student
Division of Molecular Hematology

Email: Parashar [dot] dhapola [at] med [dot] lu [dot] se

 

Find out more about the Research Group on Stem Cells and Leukemia

Publications:

Read the full scientific article “Concurrent stem- and lineage-affiliated chromatin programs precede hematopoietic lineage restriction,” in Cell Reports, 10 May, 2022.

 

Learn more about this topic through the group's previous work on "The Tetraspanin CD9 Affords High-Purity Capture of All Murine Hematopoietic Stem Cells," in Cell Reports, 29 August, 2013.