Introduction and context

In 2006, Takahashi and Yamanaka [1] reported the direct reprogramming of mouse fibroblasts to pluripotent stem cells, which were termed induced pluripotent stem cells (iPSCs). This scientific breakthrough was achieved through overexpression of the four transcription factors OCT4, SOX2, KLF4, and c-MYC [1]. The successful reprogramming of human somatic cells reported the following year [2-4] opened new frontiers for disease modelling and regenerative medicine. Since then, several methodologies, using viral, non-viral, or chemical approaches, have been devised to establish iPSCs from various mouse and human somatic cell types [5]. These include mouse cells in all stages of the hematopoietic hierarchy and human progenitor cells from cord blood, bone marrow, and peripheral blood [6-9]. It is now widely accepted that mouse and human iPSCs possess morphological, molecular, and developmental attributes that closely resemble those of blastocyst-derived embryonic stem cells (ESCs), although their global gene expression patterns and epigenetic state may not be identical [5,10]. Directed differentiation protocols already in use in ESCs were promptly applied to iPSCs, yielding numerous cell types, including neurons, cardiomyocytes, adipocytes, and endothelial and hematopoietic cells.

However, the generation of human hematopoietic stem cells (HSCs) conferring multilineage, long-term, hematopoietic reconstitution remains elusive. HSCs originate in early embryonic development, after which they expand and self-renew in successive anatomical locations. Hematopoiesis is initiated with the specification of a subset of mesodermal cells known as hemangioblasts, which yield both endothelial and hematopoietic progeny. The first hemangioblasts arise in the primitive streak of the embryo and then migrate to the yolk sac, where they form blood islands [11]. The ensuing first wave of hematopoiesis predominantly yields erythroid cells, which express embryonic and fetal globins and macrophages, but not lymphoid cells. The immediate precursors of definitive HSCs are arterial endothelial cells [12-15], which become HSCs capable of long-term multilineage repopulation of adult hosts in the dorsal aorta of the aorta-gonad-mesonephros (AGM) region and the chorioallantoic vessels of the placenta. These early CD34⁺, c-kit⁺, CD41⁺ HSCs next migrate to the placenta and mostly to the fetal liver, where their numbers further expand. Around birth, the main site of hematopoiesis shifts from liver to bone marrow, from which most blood cells originate throughout the organism’s adult life span.

Recent advances

Implications for clinical practice

The advent of iPSCs holds great promise for regenerative medicine. iPSC-based research is poised to enable a watershed of knowledge on human cell development as well as provide critical tools for disease modelling and in vitro drug screening. The potential for developing novel cell therapies is equally tantalizing but still uncertain at this time. Reprogramming technologies offer the prospect of generating blood cell types on a patient-specific basis. Thus, red blood cells could be generated for individuals with severe congenital anemias or polytransfused subjects who require a unique blood cell type. A repertoire of naïve T lymphocytes could be generated for subjects with acquired or congenital deficiencies or aging subjects afflicted by immunosenescence. However, the methods for generating such cell types are still in their infancy and marred with considerable biological, safety, and economic uncertainties. A holy grail for this field is to generate HSCs, which would open new doors for both disease correction and regenerative medicine. Two recent proof-of-principle studies highlighted the potential of combined gene and cell therapy with autologous iPSCs to treat Fanconi anemia and sickle cell disease [26,33]. Robust protocols for the directed differentiation of human iPSCs to all hematopoietic cells will provide valuable tools for modelling hematopoiesis and hematological disorders, as exemplified in a recent study on polycythemia vera [9]. However, as reviewed above, there remain significant obstacles to the generation of adult HSCs capable of long-term, pan-lineage, hematopoietic reconstitution. Further studies are also required to assess the hematopoietic potential of human iPSCs in comparison with that of ESCs [9,38-40]. Thus, the well-deserved excitement about iPSCs must be tempered with patience as a considerably larger body of basic investigation is needed to unravel the biological and therapeutic potential as well as the safety profile of iPSC-derived hematopoietic cell products.