TGF-β signaling underlies hematopoietic dysfunction and bone marrow failure in Shwachman-Diamond syndrome
Cailin E. Joyce, … , Akiko Shimamura, Carl D. Novina
Cailin E. Joyce, … , Akiko Shimamura, Carl D. Novina
Published September 3, 2019; First published June 18, 2019
Citation Information: J Clin Invest. 2019;129(9):3821-3826. https://doi.org/10.1172/JCI125375.
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Concise Communication Hematology

TGF-β signaling underlies hematopoietic dysfunction and bone marrow failure in Shwachman-Diamond syndrome

Abstract

Shwachman-Diamond syndrome (SDS) is a rare and clinically heterogeneous bone marrow (BM) failure syndrome caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. Although SDS was described more than 50 years ago, its molecular pathogenesis is poorly understood due, in part, to the rarity and heterogeneity of the affected hematopoietic progenitors. To address this, we used single-cell RNA sequencing to profile scant hematopoietic stem and progenitor cells from patients with SDS. We generated a single-cell map of early lineage commitment and found that SDS hematopoiesis was left-shifted with selective loss of granulocyte-monocyte progenitors. Transcriptional targets of transforming growth factor beta (TGF-β) were dysregulated in SDS hematopoietic stem cells and multipotent progenitors, but not in lineage-committed progenitors. TGF-β inhibitors (AVID200 and SD208) increased hematopoietic colony formation of SDS patient BM. Finally, TGF-β3 and other TGF-β pathway members were elevated in SDS patient blood plasma. These data establish the TGF-β pathway as a candidate biomarker and therapeutic target in SDS and translate insights from single-cell biology into a potential therapy.

Authors

Cailin E. Joyce, Assieh Saadatpour, Melisa Ruiz-Gutierrez, Ozge Vargel Bolukbasi, Lan Jiang, Dolly D. Thomas, Sarah Young, Inga Hofmann, Colin A. Sieff, Kasiani C. Myers, Jennifer Whangbo, Towia A. Libermann, Chad Nusbaum, Guo-Cheng Yuan, Akiko Shimamura, Carl D. Novina

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Figure 2

The cellular architecture of early hematopoiesis is altered in SDS.

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The cellular architecture of early hematopoiesis is altered in SDS. (A) ...
(A) tSNE plot of hematopoietic lineage commitment showing cells from healthy donors as in Figure 1, untreated SDS patients (SDS1.1: n = 72; SDS1.2: n = 62; SDS2.1: n = 78; N = 212), and an SDS patient who was being treated with 4.2 µg/kg/day G-CSF (SDS2.2: n = 71). Clusters were determined using the partitioning around medoids version of k-means clustering (k = 5), and labeled based on the enrichment of index-sorted HSCs, MPPs, MLPs, CMPs, GMPs, and MEPs as shown in Figure 1D. The sum of normal cells and SDS cells in each cluster is significantly changed using the χ2 test. HSCs/MPPs, orange; CMPs, pink; GMPs, blue; CLPs/MLPs, red; MEPs, green. (B) Relative frequencies of HSPC subpopulations for healthy donors and untreated SDS patients. Error bars indicate SEM.