New Insights into Hematopoietic Stem Cell Expansion to Stimulate Repopulation of the Adult Blood System for Transplantation

Abstract

Successful engraftment of hematopoietic stem cells (HSCs) and progenitor cells (HSPCs) may be considered as a basis for the repopulation of the blood cells after transplantation in adults. Therefore, in vivo and ex vivo expansion of HSCs holds great promise for clinical applications. In this review, the mechanisms of HSC expansion will be discussed, considering the previous studies and works of literature. This is aimed to identify the signaling pathways that regulate HSC expansion and improve the application of engraftment in disease management. The following aspects will be included: (i) Stimulation of HSCs growth in vivo through gene regulation and cytokines activation; (ii) direct or indirect induction of HSC expansion by regulating signaling pathways; (iii) addition to assisting cells to help in the proliferation of HSCs; (iv) changing of living environment in the HSCs cultures via adjusting components and forms of cultures; (v) enhancement of HSC expansion by incorporating substances, such as extracellular vesicles (EVs), UM171, among others. In this review, recent new findings that provide us with new insights into HSC expansion methods have been summarized. Furthermore, these findings will also provide more possibilities for the development of some novel strategies for expanding and engrafting HSCs applied for treatments of some hematopoietic disorders.

Keywords: cultures; ex vivo expansion; hematopoietic stem cells; in vivo expansion; microenvironment regulation; signaling pathway.

Figure 1

ZBTB7A acts on the process with HSCs’ differentiation and glycolytic pathways to regulate HSC expansion. In HSC differentiation, ZBTB7A mutations disturb myeloid HSCs and HSPC differentiation. In the glycolytic pathway, ZBTB7A with RUNX1-RUNX1T1 fusion gene can downregulate MYC and PKM2 to promote glycolysis and sensitize leukemic blasts.

Figure 2

Overview of signaling pathways involved in HSC expansion. Shh, GSK3, TGF-b, Notch and Hox signaling pathways are the basic pathways that regulate HSC expansion via affecting cell differentiation and circumstances. Signaling pathways have both positive and negative effects on HSC amplification.

Figure 3

Overview of substances that expand HSCs in vitro. Substances can be classified into 3 categories based on their action on HSC expansion: act by biologic molecules, act on surface phenotype (CD34+), and act on signaling pathway. Biologic molecules act by producing bioactivators to create necessary substances to expand HSCs. CD34+ is the typical phenotype that stimulates HSC expansion. The signaling pathway has been previously discussed.