Progress and obstacles towards generating hematopoietic stem cells from pluripotent stem cells

Abstract

Purpose of review Human pluripotent stem cells (PSCs) have the potential to provide an inexhaustible source of hematopoietic stem cells (HSCs) that could be used in disease modeling and in clinical applications such as transplantation. Although the goal of deriving definitive HSCs from PSCs has not been achieved, recent studies indicate that progress is being made. This review will provide information on the current status of deriving HSCs from PSCs, and will highlight existing challenges and obstacles. Recent findings Recent strides in HSC generation from PSCs has included derivation of developmental intermediates, identification of transcription factors and small molecules that support hematopoietic derivation, and the development of strategies to recapitulate niche-like conditions. Summary Despite considerable progress in defining the molecular events driving derivation of hematopoietic progenitor cells (HPCs) from PSCs, the generation of robust transplantable HSCs from PSCs remains elusive. We propose that this goal can be facilitated by better understanding of the regulatory pathways governing HSC identity, development of HSC supportive conditions, and examining the marrow homing properties of PSC-derived HSCs.

Stem cell homing: From physiology to therapeutics

“…Models such as zebra fish with easy labeling and tracking of stem cells may therefore provide valuable information about physiologic stem cell migration and homing since factors guiding these processes have been difficult to discern in mammalian systems. In mammals, one of the main obstacles to generating HSCs from pluripotent stem cells is maintaining and enhancing their homing efficiency 11 …”

Long-Term Engraftment and Fetal Globin Induction upon BCL11A Gene Editing in Bone-Marrow-Derived CD34 + Hematopoietic Stem and Progenitor Cells

“…Other novel gene therapy strategies such as correcting the sickle mutation in induced pluripotent stem cells (iPSCs)23, 24 or in primary human CD34 + hematopoietic stem and progenitor cells (HSPCs)25, 26 have been explored pre-clinically. However, fully functional HSCs have yet to be derived from iPSCs, 27 and achieving efficient levels of gene correction in long-term repopulating HSCs via homology-directed repair (HDR) pathways without utilizing a selectable marker 26 has remained challenging, 28 limiting the clinical relevance of such approaches. In contrast to HDR, gene disruption via non-homologous end joining (NHEJ) repair pathways occurs at a high frequency in HSCs 28 .…”

mRNA-mediated glycoengineering ameliorates deficient homing of human stem cell–derived hematopoietic progenitors

“…Finally, cells undergo transendothelial migration and parenchymal lodgment, processes modulated by chemokine gradients within the BM (3). Although BM homing is a critical aspect of HSPC biology, studies assessing the homing properties of HSPCs from human pluripotent stem cells are lacking (2).…”

“…Derivation of large quantities of HSPCs from human pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and/or induced pluripotent stem cells (iPSCs), holds great promise to mitigate many HSPC transplantation-related limitations. However, despite much progress, generation of fully functional and engraftmentcompetent HSPCs from human pluripotent stem cells ex vivo has remained challenging (2).…”