Nav: Home

Uncovering secrets of bone marrow cells and how they differentiate

July 31, 2019

BIRMINGHAM, Ala. - Bone marrow contains biological factories, which pump out billions of new blood cells daily. The non-blood cells that maintain this production also have the potential to produce bone, fat and cartilage. This output all starts from stem cells that have the ability to differentiate into various types of cells.

Knowledge of the genes that control this differentiation and the paths that cells take to their final, differentiated forms is an important biological question because dysregulation of this process is linked to pathologies -- such as obesity, osteoporosis, cancer, tooth loss and aging. Knowledge of the mechanisms that regulate cell differentiation could lead to improved understanding of the pathogenesis of these disorders and eventually new treatments. But the search is challenging because bone marrow is a complex mix of cells in small niches and with largely unknown interactions and relationships.

Research led by Robert Welner, Ph.D., assistant professor in the University of Alabama at Birmingham Division of Hematology and Oncology, has now mapped distinct bone marrow niche populations and their differentiation paths for the bone marrow factory that starts from mesenchymal stromal cells and ends with three types of cells -- fat cells, bone-making cells and cartilage-making cells. Respectively, those cells are called adipocytes, osteoblasts and chondrocytes. This non-hematopoietic cell system is distinct from another production line in the bone marrow -- the hematopoietic system -- that makes red blood cells, blood-clotting cells and cells of the immune system.

Welner and colleagues at UAB, Harvard Medical School and Beth Deaconess Medical Center, Boston, have published their findings in Cell Reports. Their main research tool was single-cell RNA sequencing, which identified mRNA transcripts from genes in 2,847 individual bone marrow cells of the non-hematopoietic system. By sequencing these RNAs, researchers could tell which genes had been turned on or off at different steps on differentiation pathways.

"The single-cell RNA sequencing gene expression profiles generated permit a real-time depiction of dynamic processes associated with fate choices within the bone marrow microenvironment," said Welner, who is also an associate scientist with the O'Neal Comprehensive Cancer Center at UAB. "Our study provides a landscape for a better understanding of transcriptional networks regulating differentiation of bone marrow microenvironment cells."

A major finding was a detailed characterization of three distinct paths in a simple, branching hierarchy of differentiation, starting from mesenchymal stem cells, or MSCs, and ending with pre-adipocytes, pro-osteoblasts and pro-chondrocytes. In all, they identified seven distinct cell states in two branching pathways. One branch was MSCs to adipocyte progenitors to pre-adipocytes. The other was from MSCs to osteoblast/chondrocyte progenitors to pre-osteoblasts/chondrocytes, and finally a split to either pro-osteoblasts or pro-chondrocytes.

For each of these unique subpopulations, they identified gene signatures, and they demonstrated how several transcription factors -- gene control proteins that alter the rate of transcription from DNA to mRNA -- influence fate decisions to specific bone marrow lineages. The dataset the researchers created and the analysis tools they used are publicly available and will serve as a resource for future studies investigating stromal cell differentiation.

An important control in the research, Welner says, and one that should be used in all single-cell RNA sequencing research, was validation studies. These included fate-marked reporters and knockdowns of transcription factors previously reported to govern bone and fat differentiation. The knockdowns allowed researchers to assay differentiation potential in cell culture for the lineages they identified through single-cell RNA sequencing. The validation studies by Welner and colleagues all supported the findings from their single-cell RNA sequencing.
-end-
Co-first authors with senior author Welner on the Cell Reports paper, "Mapping distinct bone marrow niche populations and their differentiation paths," were Samuel L. Wolock and Indira Krishnan, Harvard Medical School. Additional co-authors were Danielle E. Tenen, Beth Israel Deaconess Medical Center; Victoria Matkins, Virginia Camacho, Sweta Patel, Puneet Agarwal and Ravi Bhatia, Division of Hematology and Oncology, UAB Department of Medicine, UAB School of Medicine; and Daniel G. Tenen and Allon M. Klein, Harvard Medical School.

Support came from National Institutes of Health grants HL131477, CA66996, CA197697 and GM080177. Support also came from startup funds from the UAB Division of Hematology and Oncology and a bridge grant from the American Society of Hematology.

University of Alabama at Birmingham

Related Science Articles:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.
Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.
Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.
Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.
Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.
World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.
PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.
Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.
Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.
Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.
More Science News and Science Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

In & Out Of Love
We think of love as a mysterious, unknowable force. Something that happens to us. But what if we could control it? This hour, TED speakers on whether we can decide to fall in — and out of — love. Guests include writer Mandy Len Catron, biological anthropologist Helen Fisher, musician Dessa, One Love CEO Katie Hood, and psychologist Guy Winch.
Now Playing: Science for the People

#541 Wayfinding
These days when we want to know where we are or how to get where we want to go, most of us will pull out a smart phone with a built-in GPS and map app. Some of us old timers might still use an old school paper map from time to time. But we didn't always used to lean so heavily on maps and technology, and in some remote places of the world some people still navigate and wayfind their way without the aid of these tools... and in some cases do better without them. This week, host Rachelle Saunders...
Now Playing: Radiolab

Dolly Parton's America: Neon Moss
Today on Radiolab, we're bringing you the fourth episode of Jad's special series, Dolly Parton's America. In this episode, Jad goes back up the mountain to visit Dolly's actual Tennessee mountain home, where she tells stories about her first trips out of the holler. Back on the mountaintop, standing under the rain by the Little Pigeon River, the trip triggers memories of Jad's first visit to his father's childhood home, and opens the gateway to dizzying stories of music and migration. Support Radiolab today at Radiolab.org/donate.