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Review
. 2014 Sep;21(5):430-7.
doi: 10.1097/MOH.0000000000000064.

Stem cells, megakaryocytes, and platelets

Brenden W Smith  1 , George J Murphy
Affiliations
Review

Stem cells, megakaryocytes, and platelets

Brenden W Smith et al. Curr Opin Hematol. 2014 Sep.

Abstract

Purpose of review: Stem cells are an important tool for the study of ex-vivo models of megakaryopoiesis and the production of functional platelets. In this manuscript, we review the optimization of megakaryocyte and platelet differentiation and discuss the mechanistic studies and disease models that have incorporated stem cell technologies.

Recent findings: Mechanisms of cytoskeletal regulation and signal transduction have revealed insights into hierarchical dynamics of hematopoiesis, highlighting the close relationship between hematopoietic stem cells and cells of the megakaryocyte lineage. Platelet disorders have been successfully modeled and genetically corrected, and differentiation strategies have been optimized to the extent that utilizing stem cell-derived platelets for cellular therapy is feasible.

Summary: Studies that utilize stem cells for the efficient derivation of megakaryocytes and platelets have played a role in uncovering novel molecular mechanisms of megakaryopoiesis, modeling and correcting relevant diseases, and differentiating platelets that are functional and scalable for translation into the clinic. Efforts to derive megakaryocytes and platelets from pluripotent stem cells foster the opportunity of a revolutionary cellular therapy for the treatment of multiple platelet-associated diseases.

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Conflict of interest statement

Conflicts of interest

There are no conflicts of interest.

The authors have no conflicts of interest to disclose.

Figures

FIGURE 1
FIGURE 1
Idealized model of stem cell-derived treatment for platelet-related disorders. Platelets differentiated from iPSCs could be an efficacious cellular treatment derived from patient-specific donor material. iPSCs are made from the peripheral blood of affected individuals. They can then be manipulated by gene therapeutic strategies to correct the disease phenotype by genome editing and expression of the normal disease-specific allele [1▪▪,2▪▪], as well as overexpression of transgenic material [3▪▪,4▪▪,5▪,6▪▪]. Pluripotent cells would then be differentiated into megakaryocyte progenitors [7▪▪,8▪▪] and potentially immortalized via transduction of factors that inhibit apoptosis and senescence [9▪▪]. This would culminate in platelet production, which has been achieved through multiple strategies, including an embryoid body system [10▪] and from immortalized progenitors [9▪▪]. Optimization of static culture conditions [11▪] and adapting platelet differentiation to a bioreactor system [12▪▪] would promote scalable production that could be clinically efficacious. Patients would receive platelet transfusions of iPSC platelets that would be optimized to reduce immune rejection. These clinical efforts are already underway for both transfusion of megakaryocyte progenitors [13▪▪] and platelet transplant [14▪▪]. iPSC, induced pluripotent stem cell.
See this image and copyright information in PMC

References

    1. Hirata S, Takayama N, Jono-Ohnishi R, et al. Congenital amegakaryocytic thrombocytopenia iPS cells exhibit defective MPL-mediated signaling. J Clin Invest. 2013;123:3802–3814. This study uses an iPSC disease modeling approach to study CAMT, a disorder caused by loss-of-function mutations of C-mpl. CAMT iPSCs retained the disease phenotype but were corrected by retroviral delivery of normal C-mpl, effectively restoring the capacity for megakaryocyte differentiation.

    1. Sullivan SK, Mills JA, Koukouritaki SB, et al. High-level transgene expression in induced pluripotent stem cell-derived megakaryocytes: correction of Glanzmann thrombasthenia. Blood. 2013;123:753–757. This study describes a breakthrough for proof-of-principle studies of disease correction of platelet-associated disease. iPSCs were made from patients with Glanzmann thrombasthenia, a disorder caused by mutations in integrin αIIbβ3. It was only after forced expression of normal αIIb cDNA that derived megakaryocytes produced platelets with the capacity for expression and, importantly, activation of this critical megakaryocyte specific integrin complex.

    1. Chen Y, Schroeder JA, Kuether EL, et al. Platelet gene therapy by lentiviral gene delivery to hematopoietic stem cells restores hemostasis and induces humoral immune tolerance in FIX(null) mice. Mol Ther. 2014;22:169–177. This study uses lentiviral transduction to induce platelet-specific expression of FIX in murine HSCs. Transplantation into FIX-null mice led to improved coagulation in both primary and secondary transplant recipients. Importantly, anti-FIX antibodies were not detected in recipients, suggesting that this methodology would be clinically efficacious for patients with hemophilia B.

    1. Shi Q, Kuether EL, Chen Y, et al. Platelet gene therapy corrects the hemophilic phenotype in immunocompromised hemophilia A mice transplanted with genetically manipulated human cord blood stem cells. Blood. 2014;123:395–403. This study uses human CD34+ cord blood cells as a peptide delivery system for a hemophila A mouse model. After lentiviral tranduction with 2bF8, the gene for FVIII, transplanted human cord blood was found to express FVIII in engrafted platelets and to prevent mortality in recipients with greater than 2% engraftment upon challenge with a tail clip test.

    1. Yakura Y, Ishihara C, Kurosaki H, et al. An induced pluripotent stem cell-mediated and integration-free factor VIII expression system. Biochem Biophys Res Commun. 2013;431:336–341. This paper describes the forced expression of transgenic FVIII in platelets derived from murine iPSCs. iPSCs were generated using a sendai virus vector, and platelet-specific expression of FVIII was achieved by Chinese Hampster Ovary cell-dependent microcell-mediated chromosome transfer.

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