PDF(Pubmed)
Abstract：
Glomerular filtration relies on the type IV collagen (ColIV) network of the glomerular basement membrane, namely, in the triple helical molecules containing the α3, α4, and α5 chains of ColIV. Loss of function mutations in the genes encoding these chains (Col4a3, Col4a4, and Col4a5) is associated with the loss of renal function observed in Alport syndrome (AS). Precise understanding of the cellular basis for the patho-mechanism remains unknown and a specific therapy for this disease does not currently exist. Here, we generated a novel allele for the conditional deletion of Col4a3 in different glomerular cell types in mice. We found that podocytes specifically generate α3 chains in the developing glomerular basement membrane, and that its absence is sufficient to impair glomerular filtration as seen in AS. Next, we show that horizontal gene transfer, enhanced by TGFβ1 and using allogenic bone marrow-derived mesenchymal stem cells and induced pluripotent stem cells, rescues Col4a3 expression and revive kidney function in Col4a3-deficient AS mice. Our proof-of-concept study supports that horizontal gene transfer such as cell fusion enables cell-based therapy in Alport syndrome.
摘要：
肾小球滤过依赖于肾小球基底膜的IV型胶原（ColIV）网络，即,在包含ColIV的α3，α4和α5链的三螺旋分子中。编码这些链（Col4a3，Col4a4和Col4a5）的基因中功能突变的丧失与在Alport综合征（AS）中观察到的肾功能丧失有关。对病理机制的细胞基础的精确理解仍然未知，并且目前还不存在针对该疾病的特定疗法。这里,我们在小鼠不同肾小球细胞类型中产生了Col4a3条件性缺失的新等位基因。我们发现足细胞在发育的肾小球基底膜中特异性产生α3链，并且它的缺乏足以损害肾小球滤过，如AS所示。接下来,我们展示了水平基因转移，通过TGFβ1增强，并使用同种异体骨髓间充质干细胞和诱导多能干细胞，挽救Col4a3缺陷AS小鼠的Col4a3表达并恢复肾功能。我们的概念验证研究支持水平基因转移，例如细胞融合，可以在Alport综合征中进行基于细胞的治疗。
