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), our 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 Shinya 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.

Bcl11a Deficiency Leads to Hematopoietic Stem Cell Defects with an Aging-like Phenotype

“…The limited success of current strategies is due in part to the embryonic-like nature of the ESC/iPSC-derived hematopoietic cells that are developmentally restricted from becoming competent definitive HSCs. Hence, elucidating the role of transcription factors such as BCL11A in definitive hematopoiesis may provide insights into developing improved strategies to overcome these obstacles (Daniel et al, 2016). …”

Induction of developmental hematopoiesis mediated by transcription factors and the hematopoietic microenvironment

“…We refer the readers to reviews published prior to the publication of these papers for more background on this topic. [21][22][23] Herein, we take a journey through developmental hematopoiesis and highlight the TFs involved at different stages, in particular, those we use in our reprogramming (GATA2, GFI1B, FOS, and GFI1) and the environmental cues that mediate the process. There are multiple mysteries that still exist, especially in human developmental hematopoiesis.…”

Induction of human hemogenesis in adult fibroblasts by defined factors and hematopoietic coculture

“…Due to their ability to repopulate the entire hematopoietic system upon transplantation in both mice and humans, HSCs represent the currently established standard for stem cell therapy. To this end, several studies exist that employ different methods to expand these cells ex vivo or generate them de novo [10][11][12][13]. To this end, several studies exist that employ different methods to expand these cells ex vivo or generate them de novo [10][11][12][13].…”

“…The source material required for these applications, however, remains in limited supply because HSCs notoriously die or differentiate ex vivo [9]. To this end, several studies exist that employ different methods to expand these cells ex vivo or generate them de novo [10][11][12][13]. This issue hinders their use for a multitude of in vitro applications, such as drug testing platforms and disease modeling systems.…”

“…A paradigm shift in stem cell biology emerged once Yamanaka et al demonstrated that overexpression of a defined set of transcription factors (TFs) could reprogram the differentiation of somatic cells to induced pluripotent stem cells (iPSCs) [15,16]. Ectopic TF overexpression to alter cell identity translated to the field of hematopoiesis, and multiple studies used different starting mouse or human cell populations, TF combinations, or culture conditions to obtain various types of in vitro derived blood products de novo [11,12]. Several of these studies focused on using either pluripotent [17][18][19][20][21][22][23][24] or somatic [25][26][27][28][29][30] cells with varying levels of success.…”