Direct Conversion of Human Fibroblasts to Multilineage Blood Progenitors

Overview

Journal Nature

Specialty Science

Date 2010 Nov 9

PMID 21057492

Citations 333

Authors

Eva Szabo

Shravanti Rampalli

Ruth M Risueno

Angelique Schnerch

Ryan Mitchell

Aline Fiebig-Comyn

Marilyne Levadoux-Martin

Mickie Bhatia

Affiliations

Soon will be listed here.

Abstract

As is the case for embryo-derived stem cells, application of reprogrammed human induced pluripotent stem cells is limited by our understanding of lineage specification. Here we demonstrate the ability to generate progenitors and mature cells of the haematopoietic fate directly from human dermal fibroblasts without establishing pluripotency. Ectopic expression of OCT4 (also called POU5F1)-activated haematopoietic transcription factors, together with specific cytokine treatment, allowed generation of cells expressing the pan-leukocyte marker CD45. These unique fibroblast-derived cells gave rise to granulocytic, monocytic, megakaryocytic and erythroid lineages, and demonstrated in vivo engraftment capacity. We note that adult haematopoietic programs are activated, consistent with bypassing the pluripotent state to generate blood fate: this is distinct from haematopoiesis involving pluripotent stem cells, where embryonic programs are activated. These findings demonstrate restoration of multipotency from human fibroblasts, and suggest an alternative approach to cellular reprogramming for autologous cell-replacement therapies that avoids complications associated with the use of human pluripotent stem cells.

Citing Articles

The landscape of cell lineage tracing.

Feng Y, Liu G, Li H, Cheng L Sci China Life Sci. 2025; .

PMID: 40035969 DOI: 10.1007/s11427-024-2751-6.

Soft Modes as a Predictive Framework for Low Dimensional Biological Systems across Scales.

Russo C, Husain K, Murugan A ArXiv. 2025; .

PMID: 39764393 PMC: 11702803.

Protocol for the San Diego Nathan Shock Center Clinical Cohort: a new resource for studies of human aging.

Phang H, Heimler S, Scandalis L, Wing D, Moran R, Nichols J BMJ Open. 2024; 14(6):e082659.

PMID: 38925692 PMC: 11202663. DOI: 10.1136/bmjopen-2023-082659.

Dedifferentiation-like reprogramming of degenerative nucleus pulposus cells into notochordal-like cells by defined factors.

Zhang Y, Liang C, Xu H, Li Y, Xia K, Wang L Mol Ther. 2024; 32(8):2563-2583.

PMID: 38879755 PMC: 11405157. DOI: 10.1016/j.ymthe.2024.06.018.

Lineage Reprogramming: Genetic, Chemical, and Physical Cues for Cell Fate Conversion with a Focus on Neuronal Direct Reprogramming and Pluripotency Reprogramming.

Umeyama T, Matsuda T, Nakashima K Cells. 2024; 13(8.

PMID: 38667322 PMC: 11049106. DOI: 10.3390/cells13080707.

References

Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126(4):663-76. DOI: 10.1016/j.cell.2006.07.024. View

Boyer L, Lee T, Cole M, Johnstone S, Levine S, Zucker J . Core transcriptional regulatory circuitry in human embryonic stem cells. Cell. 2005; 122(6):947-56. PMC: 3006442. DOI: 10.1016/j.cell.2005.08.020. View

Orkin S, Zon L . Hematopoiesis and stem cells: plasticity versus developmental heterogeneity. Nat Immunol. 2002; 3(4):323-8. DOI: 10.1038/ni0402-323. View

Hope K, Jin L, Dick J . Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol. 2004; 5(7):738-43. DOI: 10.1038/ni1080. View

Chan E, Ratanasirintrawoot S, Park I, Manos P, Loh Y, Huo H . Live cell imaging distinguishes bona fide human iPS cells from partially reprogrammed cells. Nat Biotechnol. 2009; 27(11):1033-7. DOI: 10.1038/nbt.1580. View

Debili N, Coulombel L, Croisille L, Katz A, Guichard J, BRETON-GORIUS J . Characterization of a bipotent erythro-megakaryocytic progenitor in human bone marrow. Blood. 1996; 88(4):1284-96. View

Li C, Wong W . Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc Natl Acad Sci U S A. 2001; 98(1):31-6. PMC: 14539. DOI: 10.1073/pnas.98.1.31. View

Pfisterer P, Konig H, Hess J, Lipowsky G, Haendler B, Schleuning W . CRISP-3, a protein with homology to plant defense proteins, is expressed in mouse B cells under the control of Oct2. Mol Cell Biol. 1996; 16(11):6160-8. PMC: 231619. DOI: 10.1128/MCB.16.11.6160. View

Ghozi M, Bernstein Y, NEGREANU V, Levanon D, Groner Y . Expression of the human acute myeloid leukemia gene AML1 is regulated by two promoter regions. Proc Natl Acad Sci U S A. 1996; 93(5):1935-40. PMC: 39886. DOI: 10.1073/pnas.93.5.1935. View

10.

Koschmieder S, Rosenbauer F, Steidl U, Owens B, Tenen D . Role of transcription factors C/EBPalpha and PU.1 in normal hematopoiesis and leukemia. Int J Hematol. 2005; 81(5):368-77. DOI: 10.1532/ijh97.05051. View

11.

Emslie D, DCosta K, Hasbold J, Metcalf D, Takatsu K, Hodgkin P . Oct2 enhances antibody-secreting cell differentiation through regulation of IL-5 receptor alpha chain expression on activated B cells. J Exp Med. 2008; 205(2):409-21. PMC: 2271016. DOI: 10.1084/jem.20072049. View

12.

Amariglio N, Hirshberg A, Scheithauer B, Cohen Y, Loewenthal R, Trakhtenbrot L . Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med. 2009; 6(2):e1000029. PMC: 2642879. DOI: 10.1371/journal.pmed.1000029. View

13.

Shivdasani R, Mayer E, Orkin S . Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature. 1995; 373(6513):432-4. DOI: 10.1038/373432a0. View

14.

Feugier P, Bensoussan D, Girard F, Alla F, Schuhmacher A, Latger-Cannard V . Hematologic recovery after autologous PBPC transplantation: importance of the number of postthaw CD34+ cells. Transfusion. 2003; 43(7):878-84. DOI: 10.1046/j.1537-2995.2003.00446.x. View

15.

Silverstein S, Steinman R, COHN Z . Endocytosis. Annu Rev Biochem. 1977; 46:669-722. DOI: 10.1146/annurev.bi.46.070177.003321. View

16.

Hassan H, Zander A . Stem cell factor as a survival and growth factor in human normal and malignant hematopoiesis. Acta Haematol. 1996; 95(3-4):257-62. DOI: 10.1159/000203893. View

17.

Kim J, Greber B, Arauzo-Bravo M, Meyer J, Park K, Zaehres H . Direct reprogramming of human neural stem cells by OCT4. Nature. 2009; 461(7264):649-3. DOI: 10.1038/nature08436. View

18.

Jaenisch R, Young R . Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell. 2008; 132(4):567-82. PMC: 4142810. DOI: 10.1016/j.cell.2008.01.015. View

19.

Sridharan R, Tchieu J, Mason M, Yachechko R, Kuoy E, Horvath S . Role of the murine reprogramming factors in the induction of pluripotency. Cell. 2009; 136(2):364-77. PMC: 3273494. DOI: 10.1016/j.cell.2009.01.001. View

20.

Roy N, Cleren C, Singh S, Yang L, Beal M, Goldman S . Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat Med. 2006; 12(11):1259-68. DOI: 10.1038/nm1495. View