Converting cell fates: generating hematopoietic stem cells de novo via transcription factor reprogramming

Abstract

Even though all paradigms of stem cell therapy and regenerative medicine emerged from the study of hematopoietic stem cells (HSCs), the inability to generate these cells de novo or expand them in vitro persists. Initial efforts to obtain these cells began with the use of embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) technologies, but these strategies have yet to yield fully functional cells. Subsequently, more recent approaches involve transcription factor (TF) overexpression to reprogram PSCs and various somatic cells. The induction of pluripotency with just four TFs by Yamanaka informs our ability to convert cell fates and demonstrates the feasibility of utilizing terminally differentiated cells to generate cells with multilineage potential. In this review, we discuss the recent efforts undertaken using TF-based reprogramming strategies to convert several cell types into HSCs.

Keywords: cell fate conversion; hematopoiesis; hematopoietic stem cells; reprogramming; transcription factors.

Figure 1

Established TF reprogramming strategies. TF reprogramming has been shown to work across a variety of cell types. This figure shows the starting and end cell populations, as well as the TF cocktails used to derive each cell type of choice. Adapted from Ref. .

Figure 2

Paradigm for HSPC reprogramming and clinical application. This figure displays the overall goals of HSPC reprogramming, and the most prevalent ways that this work will be applied to both research and medicine. The ideal strategy is to effectively reprogram patient cells and use them for studying hematopoiesis, drug discovery, and stem cell medicine.

Figure 3

Timeline of attempted HSPC derivation strategies. From a variety of different mouse and human strategies, laboratories have been trying to derive functional HSPCs, with different levels of success. This timeline shows the TF overexpression strategies that attempt to generate HSPCs de novo.

Figure 4

TF reprogramming strategies to obtain HSPCs. Investigators have attempted to generate HSPCs de novo for several years. This figure shows the multiple efforts made to obtain these cells, and the results of their reprograming strategies based on the starting cell population and the TF cocktail. The colors of the boxed TF cocktails and arrows represent the associated strategy. An H or an M at the bottom right hand corner of each TF box denotes strategies that used human or mouse cells, respectively.