Introduction to a review series on hematopoietic stem cells

The continuous regeneration of the blood from elements of the bone marrow has been a source of fascination for scientists and clinicians since the first pathologists gazed down their microscopes upon the beautiful and diverse cell types of the hematopoietic system. Although the presence of hematopoietic stem cells (HSCs) was postulated in the 1800s, the development of colony assays and transplantation assays in the 1950s enabled the establishment of functional definitions and finally made the activity of HSCs quantifiable and their study feasible. HSCs have been studied intensely since then.

Over the past 15 years, a number of technological advances have accelerated research on the identity of stem cells and their progeny and the intrinsic and extrinsic modes through which they are regulated. In addition, progress has been made toward the long-sought goal of generating HSCs de novo from embryonic or adult tissues. The following series of reviews describes the latest advances in these areas and highlights some of the new opportunities for progress in the coming decade:

• Connie J. Eaves, “Hematopoietic stem cells: concepts, definitions, and the new reality”

• Berthold Göttgens, “Regulatory network control of blood stem cells”

• Philip E. Boulais and Paul S. Frenette, “Making sense of hematopoietic stem cell niches”

• Susumu Goyama, Mark Wunderlich, and James C. Mulloy, “Xenograft models for normal and malignant stem cells”

• Linda T. Vo and George Q. Daley, “De novo generation of HSCs from somatic and pluripotent stem cell sources”

Remarkably, we continue to revise our view of the HSC. Two decades ago, techniques such as retroviral marking allowed HSCs and their progeny to be tracked in vivo. These experiments unequivocally supported the existence of the stem cell and established our current views of the kinetics and stability with which they contribute to hematopoiesis over time. Now, these views are being dramatically revised because we can observe HSC activity by using new marking strategies to study HSCs with or without transplantation. An overview of the history and current status of our understanding of HSCs, grounded in murine HSC biology, is presented by Connie J. Eaves.

Sound functional definitions of HSCs have allowed enhanced purification of HSCs, which in turn facilitates study of intrinsic and extrinsic regulation. The study of the gene networks involved in stem cell decision-making has advanced along with molecular approaches such as gene expression profiling and localization of histones and transcription factors throughout the genome. These approaches are leading to a greatly enhanced understanding of how competing molecular signals are integrated, which influences outcomes in terms of HSC differentiation and self-renewal. These advances are reviewed by Berthold Göttgens.

The past decade has also seen an increasing appreciation of the role that the microenvironment, or the niche, plays in regulating HSC function. The development of mouse lines in which individual lineages of cells in the bone marrow are labeled, along with advances in imaging technologies, has facilitated progress toward understanding the specific interactions of HSCs. These insights, reviewed by Philip E. Boulais and Paul S. Frenette, will lead to an appreciation of how the niche influences the response of HSCs to the demands of hematopoiesis and the contributions of the niche to pathogenic states.

Great strides have been made in understanding the mechanisms that regulate murine HSCs, but the study of human HSCs has lagged behind, partly because of the lack of good models for their study despite the decades-long use of mouse xenografting to support human hematopoietic cell growth. Better understanding of the immunologic barriers to supporting human cells in mice has allowed the development of new mouse models that can now be exploited. These models and their use for studying normal and malignant hematopoiesis are reviewed by Susumu Goyama, Mark Wunderlich, and James C. Mulloy.

Ultimately, hematopoietic transplantation would ideally become independent of large amounts of donor cells. This would be possible if we could generate engraftable stem cells for bone marrow transplantation. Despite early successes in generating small amounts of differentiated blood cells from embryonic stem cells, this goal has proved more challenging than expected for a variety of reasons. As work has progressed, induced pluripotent stem cells were discovered, and approaches for directly generating hematopoietic cells from nonpluripotent cell types have emerged. Although replacement of donor tissues is still some way off, the advances in de novo generation of hematopoietic cells are transforming our views about HSC identity and development. Linda T. Vo and George Q. Daley review recent progress in this area.

Together, these expert reviews provide a perspective on the last decade of work in HSC biology and lay out the directions for future work. We hope you find this review series of interest.