TC1(C8orf4) Regulates Hematopoietic Stem/Progenitor Cells and Hematopoiesis

Abstract

Hematopoiesis is a complex process requiring multiple regulators for hematopoietic stem/progenitor cells (HSPC) and differentiation to multi-lineage blood cells. TC1(C8orf4) is implicated in cancers, hematological malignancies and inflammatory activation. Here, we report that Tc1 regulates hematopoiesis in mice. Myeloid and lymphoid cells are increased markedly in peripheral blood of Tc1–deleted mice compared to wild type controls. Red blood cells are small-sized but increased in number. The bone marrow of Tc1 −/− mice is normocellular histologically. However, Lin−Sca-1+c-Kit+ (LSK) cells are expanded in Tc1 −/− mice compared to wild type controls. The expanded population mostly consists of CD150−CD48+ cells, suggesting the expansion of lineage-restricted hematopoietic progenitor cells. Colony forming units (CFU) are increased in Tc1 −/− mice bone marrow cells compared to controls. In wild type mice bone marrow, Tc1 is expressed in a limited population of HSPC but not in differentiated cells. Major myeloid transcriptional regulators such as Pu.1 and Cebpα are not up-regulated in Tc1 −/− mice bone marrow. Our findings indicate that TC1 is a novel hematopoietic regulator. The mechanisms of TC1-dependent HSPC regulation and lineage determination are unknown.

Adipose tissue hyperplasia with enhanced adipocyte-derived stem cell activity in Tc1(C8orf4)-deleted mice

“…MEFs are undifferentiated mesenchymal cells that may share stem cell-like characters. In our previous study, Tc1 −/− mice showed enhanced hematopoietic activity, but no enhancement of known hematopoietic growth factors was detected in bone marrow 29 . Together with data of this study, it might be postulated that Tc1 regulates bone marrow mesenchymal stem cell, which supports not only hematopoietic activity but also diverse systemic replenishment including adipose tissue 37 .…”

“…Tc1 -deleted mice were described previously 29 . They had been backcrossed to C57BL/6 mice for 10 generations and kept in specific pathogen-free (SPF) animal facility at the Asan Institute for Life Sciences, Seoul, Korea.…”

“…We have reported previously that Tc1 -deleted mice show increased white cells in peripheral blood and enhanced hematopoietic activity 29 . Here, we report a novel biological role of Tc1 in adipose tissue, stem cell, and metabolic regulation.…”

Thyroid cancer 1 (C8orf4) shows high expression, no mutation and reduced methylation level in lung cancers, and its expression correlates with β-catenin and DNMT1 expression and poor prognosis

“…The present study observed that the expression of TC1, β-catenin, and DNMT1 were correlated with each other, indicating that these three proteins might promote the activity of the Wnt signaling pathway in a synergistic manner. Recent studies revealed that TC1 plays a role in the regulation of stem cells, such as hematopoietic stem cells [ 16 ], adipocyte-derived stem cells [ 29 ], and liver cancer stem cells [ 22 ] via the Wnt/β-catenin signaling pathway or Notch signaling pathway. Therefore, TC1 may participate in tumorigenesis and the transformation of cancer stem cells, which require further studies.…”

“…TC1 is involved in the mitogen-activated ERK1/2 signaling pathway and promotes the G1- to S-phase transition of the cell cycle [ 15 ]. Recently, TC1 was also reported as a novel hematopoietic regulator in mice [ 16 ].…”