American Society of Hematology

Stem Cell Biology and Regenerative Medicine: Development and Differentiation of 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 successfully applied to stem cells from many other tissues, 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. The introduction of this clinical procedure has resulted in significant improvements in cure rates for both malignant and non-malignant disorders. 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.

While options for hematopoietic cell transplantation continue to expand, now including increased use of umbilical cord blood (UCB) and haplo-identical transplantation, our understanding of basic HSC biology remains limited. Strategies to improve use of gene corrected HSCs to better treat diseases such as sickle cell anemia and congenital immunodeficiencies have also been slow for wide-spread clinical translation. Research in the following areas will help achieve these priorities.

1.1Characterize HSC development and differentiation in transplantation and non-transplantation systems using complementary experimental models (human, mouse, zebrafish, etc.). This priority includes age-related clonal HSC changes and differences in developmental potential of HSCs that affect growth of immune cells that may lead to disease susceptibility.
1.2Improve strategies for HSC mobilization to enable collection of HSCs suitable for autologous transplantation and gene therapy.
1.3Characterize HSC niche components to enable improved HSC expansion and HSC mobilization strategies (as referenced in point 1.2).
1.4Use human pluripotent stem cells, both human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) for derivation of HSCs capable of long-term, multi-lineage engraftment. Gene editing of iPSCs combined with development of transplantable HSCs provides a unique opportunity to better treat and cure patients with genetic diseases that affect hematopoietic function.
1.5Develop novel assays for the assessment of safety of HSC-based therapies necessary for broader clinical use. This may include assessment at the genetic and epigenetic level.
1.6Improve gene editing of HSCs isolated from bone marrow or peripheral blood.

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 UCB transplantation, where low numbers of stem cells are directly related to delayed hematopoietic and immune reconstitution.

Improved HSC expansion strategies may significantly affect 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 priorities.

2.1The 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.
2.2The 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 and environmental mechanisms that underlie aging will aid in the development of novel therapeutic strategies for stem cell transplantation.
2.3Novel 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.

Improved characterization and understanding of human pluripotent stem cells, both human embryonic stem cells and iPSCs, provide a unique opportunity to produce specific human blood cell populations suitable for diverse therapies.

3.1The generation of megakaryocytes for patient-specific platelet production from iPSCs will drive progress in this area. Creating 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. Immortalized megakaryocytes could potentially provide a stable supply for platelets.
3.2Production 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.
3.3Safety 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.
3.4Improved availability of clinical grade and differentiated hESC and iPSC lines would facilitate hESC/iPSC blood cell production.
3.5Induced megakaryocytes, through direct conversion from other cell types, could provide a potential novel source of platelets.
3.6Development of lymphocytes (T cells and NK cells) from hESCs/iPSCs can enable development of new immunotherapies against hematopoietic malignancies.
3.7Development of myeloid cells (monocytes, granulocytes, dendritic cells, etc.) from hESCs/iPSCs can provide new strategies to treat genetic deficiencies and improve immune therapies.

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