Hematopoietic stem cells (HSCs) are at the forefront of regenerative medicine by virtue of their potential to reestablish hematopoiesis through self-renewal and differentiation upon transplantation. Extensively studied for the past 50 years, HSCs biology has laid many paradigms of adult tissue-specific stem cells.  Given the paucity of HSCs in human and murine bone marrow, an array of immunophenotypic markers are used to identify and isolate them. Immunophenotypic identity of HSCs varies greatly during ontogeny, location, upon mobilization and under ex vivo culture. This limits our understanding of HSC regulation, self-renewal, ex vivo maintenance, expansion and differentiation.

Genetic labeling of cells using gene-specific reporter expression is a great genetic tool to identify, mark and track a specific cell-type in vivo. A team of scientists led by Dr. Derrick Rossi at PCMM, Boston Children’s Hospital set out to identify set of genes that are specifically expressed within HSC compartment. Using a large number of microarray data sets of every cell types of murine hematopoietic system, the Rossi lab found a set of 40 plus genes with HSC-restricted expression. From this set of genes, post-doctoral fellows Roi Gazit and Pankaj K. Mandal, the lead authors of the study, targeted one such HSC-specific gene, Fgd5, by knocking in a reporter cassette into the endogenous Fgd5 locus to generate knock-in reporter mouse strain with HSC-restricted expression. The findings published in the latest issue of The Journal of Experimental Medicine (Volume 211 (7) 1315-1331) demonstrate that reporter expression faithfully and near-exclusively marks HSCs in murine bone marrow with reporter expression correlating with the well established immunophenotypic markers used to identify and isolate HSCs.

Dr. Rossi points to the importance of Fgd5 HSC-specific reporter strains of mice for hematopoietic stem cell community, “This is the first HSC-specific genetic resource developed, and I believe it will become a very widely used genetic tool for studying HSC biology to provide insights into improving their therapeutic potential”. Rossi and colleague also developed Tamoxifen-inducible Cre recombinase (CreERT2) knock-in strain of mice at the Fgd5 locus to permit ablation of genes specifically within HSC-compartment. “This will be very helpful in studying the role of various genes in HSC biology and will allow lineage tracing during ontogeny and differentiation process” explains Pankaj K. Mandal, one of the lead authors of the study. Ultimately, Rossi and colleagues think that HSC-reporter strain they’ve developed will be useful in identifying the conditions for expansion of HSCs outside the body, which could have significant potential for HSC transplantation procedures.