Ex vivo expansion of hematopoietic stem cells: from cord blood to induced pluripotent cells

Abstract

The hematopoietic system is one of the most rapidly renewing systems in the body. Hundreds of billions of blood cells are produced daily in adults, and maintaining this process depends on a small population of hematopoietic stem cells (HSCs). HSCs, which support adult hematopoiesis, are formed in the fetal liver and then in the bone marrow. At birth, many HSCs enter the umbilical cord blood. HSCs are capable of regenerating cells of all hematopoietic lineages, making them the basis of transplant hematology. Blood is not just a tissue, but a system for continuous, mass cell production. Therefore, the idea of creating a controlled source of HSCs in the laboratory seems logical. If cells in the body can maintain such a flow, then their artificial expansion could significantly expand the possibilities of blood transfusion, transplantation, gene therapy, and regenerative medicine. However, the same biological properties that make HSCs valuable for therapy—high proliferative potential, the ability to remain dormant, and multilineage differentiation—have become the main obstacle to their expansion outside the body. In the body, HSCs are regulated by a complex system of signals: niche cells, the extracellular matrix, cytokines, chemokines, oxygen levels, and contact interactions. Successful expansion of HSCs outside the body requires reproducing not just individual signals, but the complex regulation of their self-renewal and differentiation. Although most existing protocols can increase the number of CD34+ cells, considered HSCs, or their short-lived progeny, they do not provide sufficient numbers of functional, long-term repopulating HSCs. Induced pluripotent stem cells (iPSCs) are changing the scope of the task but do not yet address its main biological limitation: the reproduction of adult definitive HSCs. The primary objective of this review is to analyze the successes and challenges of expanding the desired number of HSCs ex vivo.