American Society of Hematology

Stem Cell Biology and Regenerative Medicine: Reprogramming Adult Stem Cells and Differentiating Stem Cells for Replacement Tissue Products

Hematologists have studied the basic biology of stem cells for decades, exploring their extensive potential to repair damaged tissue, fight infections, and reduce autoimmune diseases. The techniques and principles used by hematologists have been applied to stem cells from many other tissues with great success, spawning a large-scale stem cell research effort around the world.

Research on hematopoietic stem cells (HSCs) has led to significant clinical applications. For instance, HSC transplantation has become the single modality with curative potential for both genetic diseases and hematologic malignancies. Indeed, the introduction of this clinical procedure has resulted in significant improvements in cure rates for both malignant and non-malignant disorders. Looking to the future, the broad application of stem cells can be further optimized to advance the treatment of a variety of diseases.

Maximizing the Promise of Stem Cell and Regenerative Medicine: Priorities for Future Progress
New insights and technologies have the potential to optimize the use of stem cells and regenerative medicine, creating "designer" cells that will redefine approaches to the diagnosis and treatment of hematologic diseases.

Since stem cell numbers in the graft are important for clinical outcome following transplantation, methods to expand hematopoietic stem cells have been examined extensively. This is particularly relevant in umbilical cord blood (UCB) transplantation, where low numbers of stem cells are directly related to delayed hematopoietic and immune reconstitution.

Improved HSC expansion strategies may significantly impact transplantation outcome, enabling broader applications for UCB transplantation. These strategies are also needed to realize the full therapeutic potential of genome editing technologies to correct hematopoietic stem cells derived from patients with congenital hematologic disorders. Efforts to expand HSCs in cytokine-supported liquid cultures have been largely unsuccessful, and there is now general agreement that efficient expansion requires an appropriate context that is provided by the hematopoietic stem cell niche. A series of research programs will help achieve these important priorities.

1.1The assessment of stem cell function is still primarily defined by the cells’ ability to engraft following transplantation. The development of humanized mouse models that predict stem cell function in patients would allow relevant mechanistic studies regarding regulation of stem cell function by the niche.
1.2The process of aging has a negative impact on several HSC functions, including loss of self-renewal potential and homing. A better understanding of the cell-intrinsic as well as environmental mechanisms that underlie aging will aid in the development of novel therapeutic strategies for stem cell transplantation.
1.3Novel expansion procedures rely on the use of cellular support systems (i.e., mesenchymal stem cells) that mimic the niche. Studies must evaluate how niche signals regulate stem cell function to optimize this process for cell expansion.

Recently, reprogramming of adult stem cells has resulted in the generation of induced pluripotent stem cells (iPSCs) that can develop into any tissue of the body. These iPSCs ultimately may be used as a transplantable source of stem cells for a variety of diseases. This technology has allowed the generation of patient-specific or disease-specific stem cells that are also amenable to genetic manipulation, but recapitulation of the blood system from iPSCs is still elusive.

A major scientific hurdle is the creation of clinically meaningful advances in differentiating iPSCs into functional blood products, including transplantable HSCs with self-renewal and multi-lineage differentiation capacity.

2.1The generation of megakaryocytes for patient-specific platelet production from iPSCs will drive significant progress in this area. Creation of designer blood cells for transfusion into individuals with rare blood cell antigens that are targeted by antibodies for destruction would contribute significantly to improved care strategies.
2.2Production of red blood cells derived from autologous iPSCs could replace allogeneic products in highly immunized patients. Disease-specific iPSCs could serve as targets for both drug development and drug screening in patients with rare hematologic disorders.
2.3Safety issues, such as insertional mutagenesis and teratoma formation, represent a major concern in the development of iPSC-derived regenerative therapies, and the generation of insertion-free iPSCs and the use of relatively mature cells may reduce these risks. Extensive and long-term preclinical in vivo studies in immune-deficient mice must be completed before clinical application.

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