Protein Reprograms Differentiated Blood Stem Cells Into Multipotent State

By Marilynn Larkin

December 17, 2020

NEW YORK (Reuters Health) - BAZ2B has been identified as a master regulator protein that can reprogram differentiated blood stem cells back into a multipotent state, potentially expanding the supply of these life-saving cells, researchers say.

"Hematopoietic stem cells (HSCs) are pluripotent and can regenerate the entire blood lineage. However, reprogramming broadly available differentiated blood cells to the HSC state is challenging and requires complex genetic manipulation with a cocktail of multiple genes," Dr. Andrea Califano of Columbia University Medical School in New York City and Dr. Maria Pia Cosma of the Barcelona Institute of Science and Technology in Spain told Reuters Health by email.

"We were able to identify a single transcription factor that can reprogram committed progenitor cells - which are broadly available from cord blood, bone marrow aspirates, and even peripheral blood - to the HSC state," they said. "Importantly, we also proved that Baz2B can expand hematopoietic progenitor cells, which are normally isolated from bone marrow or umbilical cord blood and which are typically in a scarce number not sufficient to be transplanted."

For the Cell Reports study, the team used an algorithm called VIPER to identify master regulator proteins capable of reprogramming committed human B cells to a multipotent state. Out of eight potential candidates identified by the algorithm, one - the BAZ2B gene- was able to expand significantly the number of HSCs in umbilical cord blood.

BAZ2B was able to reprogram the blood stem cells to an HSC-like state by rearranging their chromatin, opening up unique regions in the genome that were previously inaccessible and, according to the authors, "significantly enhancing the long-term clonogenicity, stemness, and engraftment (of these cells) in immunocompromised mice."

"Importantly," the authors note, "this method can be used to study any reprogramming event that can be followed over time either in bulk population or in single cells."

Drs. Califano and Cosma said, "This could have far-reaching implications, from the ability of regenerating the blood of a patient on an ongoing basis to allowing bone marrow regeneration in a leukemia patient from cells selected not to present any abnormalities... And, equally important, this paper shows how analysis of regulatory networks via network-based algorithms can pinpoint with extreme accuracy the handful of genes that can transdifferentiate cells between two states - in this case from a differentiated to a pluripotent state."

"The first clinic-ready applications to expand or reprogram multipotent and/or committed progenitors could arrive in in the next five years," they conclude.

Dr. Betsy Barnes, a professor in the Institute of Molecular Medicine at The Feinstein Institutes for Medical Research in Manhasset, New York, called the findings "compelling."

Nonetheless, she said, "Engraftment efficiency in mice, which are an inbred species, already show quite a bit of variability across donor samples. Given that humans are a highly variable species and not genetically inbred, there remains a question of how human variation will contribute to engraftment efficiency. Also, a caveat to many of these types of technologies is the feasibility of scaling up the cultures to treat human disease."

"Transitioning to fully human studies and possibly the utilization of CRISPR-Cas9 rather than an inducible lentiviral system to turn on genes that drive HSC expansion... may help to reduce variability in engraftment efficiency," she said.

Dr. Califano is a funder and shareholder of DarwinHealth, which was granted an exclusive license by Columbia University for the commercialization of algorithms used in this study. Columbia University is a shareholder in the company. A provisional patent was granted to Drs. Cosma and Califano and another coauthor.

SOURCE: https://bit.ly/2WozW5s Cell Reports, online December 8, 2020.

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