Division of Hematology and Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.
J Clin Invest. 2022 Jun 15;132(12). doi: 10.1172/JCI155914.
The crosstalk between the BM microenvironment (niche) and hematopoietic stem cells (HSCs) is critical for HSC regeneration. Here, we show that in mice, deletion of the Fanconi anemia (FA) genes Fanca and Fancc dampened HSC regeneration through direct effects on HSCs and indirect effects on BM niche cells. FA HSCs showed persistent upregulation of the Wnt target Prox1 in response to total body irradiation (TBI). Accordingly, lineage-specific deletion of Prox1 improved long-term repopulation of the irradiated FA HSCs. Forced expression of Prox1 in WT HSCs mimicked the defective repopulation phenotype of FA HSCs. WT mice but not FA mice showed significant induction by TBI of BM stromal Wnt5a protein. Mechanistically, FA proteins regulated stromal Wnt5a expression, possibly through modulating the Wnt5a transcription activator Pax2. Wnt5a treatment of irradiated FA mice enhanced HSC regeneration. Conversely, Wnt5a neutralization inhibited HSC regeneration after TBI. Wnt5a secreted by LepR+CXCL12+ BM stromal cells inhibited β-catenin accumulation, thereby repressing Prox1 transcription in irradiated HSCs. The detrimental effect of deregulated Wnt5a/Prox1 signaling on HSC regeneration was also observed in patients with FA and aged mice. Irradiation induced upregulation of Prox1 in the HSCs of aged mice, and deletion of Prox1 in aged HSCs improved HSC regeneration. Treatment of aged mice with Wnt5a enhanced hematopoietic repopulation. Collectively, these findings identified the paracrine Wnt5a/Prox1 signaling axis as a regulator of HSC regeneration under conditions of injury and aging.
骨髓微环境（龛）与造血干细胞（HSCs）之间的串扰对于 HSC 再生至关重要。在这里，我们表明，在小鼠中，范可尼贫血（FA）基因 Fanca 和 Fancc 的缺失通过对 HSCs 的直接影响和对 BM 龛细胞的间接影响来抑制 HSC 再生。FA HSCs 在全身照射（TBI）后持续上调 Wnt 靶基因 Prox1。因此，Prox1 的谱系特异性缺失改善了照射 FA HSCs 的长期重编程。在 WT HSCs 中强制表达 Prox1 模拟了 FA HSCs 缺陷的重编程表型。WT 小鼠而非 FA 小鼠在 TBI 后表现出 BM 基质 Wnt5a 蛋白的显著诱导。从机制上讲，FA 蛋白调节基质 Wnt5a 的表达，可能通过调节 Wnt5a 转录激活因子 Pax2。Wnt5a 处理照射的 FA 小鼠增强了 HSC 再生。相反，Wnt5a 中和抑制 TBI 后 HSC 再生。LepR+CXCL12+BM 基质细胞分泌的 Wnt5a 抑制 β-catenin 积累，从而抑制照射 HSCs 中 Prox1 的转录。在 FA 患者和老年小鼠中也观察到失调的 Wnt5a/Prox1 信号对 HSC 再生的有害影响。照射诱导老年小鼠 HSCs 中 Prox1 的上调，并且老年 HSCs 中 Prox1 的缺失改善了 HSC 再生。用 Wnt5a 处理老年小鼠增强了造血重编程。总之，这些发现确定了旁分泌 Wnt5a/Prox1 信号轴作为损伤和衰老条件下 HSC 再生的调节剂。
