Good news in biomedicine is published today in the prestigious journal Cell Reports. The study shows that is possible to convert skin cells into megakaryocytes with the same functions that the ones that are in the human body, able to produce platelets, the blood cell type responsible of the normal blood clotting. This conversion was induced by a cocktail of 6 factors and takes only 2 weeks. The cells generated in this way were successfully transplanted into mice, giving rise to normal platelets in the animals. Also, the researchers combined this protocol with gene therapy in skin cells of patients with reduced number of platelets, and showed that normal, disease-free platelets could be generated in the laboratory. This work, led by Ángel Raya (ICREA Research Professor at the CMR[B] and member of CIBER-BBN) opens new avenues for producing cells with potential benefit for patients in a fast and efficient manner.
Current sources of platelets for transfusion are insufficient and can be associated with risk of immune rejection and blood infections. Looking for an alternative to conventional transfusions of external platelets, the authors used a technology recently developed in collaboration with researchers at Lund University in Sweden (published 3 months ago, also in Cell Reports) for generating red blood cells. In the study published today, CMR[B] researchers pushed this technology further and succeeded at producing megakaryocytes, which can be used in the laboratory to generate platelets. Alternatively, megakaryocytes produced in this way can be transplanted into animals, where they engraft and differentiate, giving rise to functional platelets that circulate in the blood of mice together with their own platelets.
To test the clinical applicability of this conversion protocol, the authors turned to a context in which generating megakaryocytes would be clinically relevant. Fanconi anemia is a rare genetic disease in which most of the patients suffer from severe reduced numbers of platelets. In collaboration with the group of Juan Bueren at CIEMAT in Madrid, member of CIBERER and a worldwide expert in this disease, the researchers used the new method on skin cells from Fanconi anemia patients. After genetic correction of the patients’ cells, the 6-factor cocktail was able to convert them into disease-free megakaryocytes, which in turn could be used to produce healthy platelets in the laboratory.
“The results of our study demonstrate that megakaryocytes with clinical potential can be obtained by direct transdifferentiation of easily accessible samples such as skin cells, as an alternative to the generation of induced pluripotent stem cells (iPSC). Which technology will eventually be used in the clinical setting (if any) is hard to predict, but direct transdifferentiation is definitely faster, cheaper, and more efficient. At any rate, the fact that we can completely change the identity of a fibroblast and convert it into a megakaryocyte with just 6 factors is mechanistically still poorly understood, but biologically amazing”, underlines Ángel Raya.
Although this study is a very big step towards the clinical translation of this kind of treatments, much more research is needed to ensure the safety and efficiency for patients.
“This study is the product of an intense and fruitful collaboration project among several groups and is an important step towards the generation of human blood megakaryocytes and platelets with direct clinical applications. Further studies should allow an improvement in the efficiency and the safety of this system”, adds Julián Pulecio, first author of the study.
The Center of Regenerative Medicine in Barcelona (CMR[B]) is a research center created in 2006 through an agreement between the Catalan Government's Ministry of Health and the Carlos III Healthcare Institute (ISC IIII). The CMR[B]’s mission is to carry out fundamental research of excellence for advancing the clinical translation of regenerative medicine. Since 2008, the CMR[B] has focused its efforts in the field of somatic cell reprogramming, becoming a worldwide reference for the generation of patient-specific iPS cells for cell therapy and in vitro disease modeling.
This research has been possible thanks to the partial support to Julián Pulecio by the Juan de la Cierva program (MINECO) and the additional support provided by grants from MINECO (SAF2015-69706-R), ISCIII/FEDER (Red de Terapia Celular – TerCel RD12/0019/0019 and RD12/0019/0023), AGAUR (2014-SGR-1460), Fundació La Marató de TV3 (201534-30).
Julián Pulecio, Oriol Alejo, Sandra Capellera-Garcia, Marianna Vitaloni, Paula Río, Eva Mejía-Ramírez, Ilaria Caserta, Juan A. Bueren, Johan Flygare, Ángel Raya (2016). Direct conversion of fibroblasts to megakaryocyte progenitors. Cell reports
Center of Regenerative Medicine in Barcelona (CMR[B], Barcelona, Spain), Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN, Madrid, Spain), Lund Stem Cell Centre (Lund University, Lund, Sweden), Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT, Madrid, Spain), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, Madrid, Spain), Fundación Jiménez Díaz (UAM, Madrid, Spain), Institució Catalana de Recerca i Estudis Avançats (ICREA, Barcelona, Spain).