Lamins regulate cell trafficking and lineage maturation of adult human hematopoietic cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-11, Vol.110 (47), p.18892-18897
• Main Authors: Shin, Jae-Won, Spinler, Kyle R., Swift, Joe, Chasis, Joel A., Mohandas, Narla, Discher, Dennis E.
• Format: Article
• Language: English
• Subjects: Adult Stem Cells - cytology; Adult Stem Cells - physiology; adults; Biological Sciences; Biophysics; Blood; Blood cells; Bone marrow; Cell Lineage - physiology; Cell lines; Cell Movement - physiology; Cell nucleus; Cell Nucleus - metabolism; erythroblasts; Erythropoiesis - physiology; Flow cytometry; Flow Cytometry - methods; gene overexpression; Hematopoietic stem cells; Humans; Lamins; Lamins - metabolism; Mass spectrometry; Mass Spectrometry - methods; megakaryocytes; micropores; Physical Sciences; ploidy; porous media; Progenitor cells; Proteins; retinoic acid; Rheology; Stem cells; stoichiometry; T lymphocytes; Thrombopoiesis - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1304996110

Hematopoietic stem and progenitor cells, as well as nucleated erythroblasts and megakaryocytes, reside preferentially in adult marrow microenvironments whereas other blood cells readily cross the endothelial barrier into the circulation. Because the nucleus is the largest organelle in blood cells, we hypothesized that (i) cell sorting across microporous barriers is regulated by nuclear deformability as controlled by lamin-A and -B, and (ii) lamin levels directly modulate hematopoietic programs. Mass spectrometry-calibrated intracellular flow cytometry indeed reveals a lamin expression map that partitions human blood lineages between marrow and circulating compartments (P = 0.00006). B-type lamins are highly variable and predominate only in CD34 ⁺ cells, but migration through micropores and nuclear flexibility in micropipette aspiration both appear limited by lamin-A:B stoichiometry across hematopoietic lineages. Differentiation is also modulated by overexpression or knockdown of lamins as well as retinoic acid addition, which regulates lamin-A transcription. In particular, erythroid differentiation is promoted by high lamin-A and low lamin-B1 expression whereas megakaryocytes of high ploidy are inhibited by lamin suppression. Lamins thus contribute to both trafficking and differentiation.