A neovascularized organoid derived from retrovirally engineered bone marrow stroma leads to prolonged in vivo systemic delivery of erythropoietin in nonmyeloablated, immunocompetent mice
A neovascularized organoid derived from retrovirally engineered bone marrow stroma leads to prolonged in vivo systemic delivery of erythropoietin in nonmyeloablated, immunocompetent mice
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DOI：
10.1038/sj.gt.3301919
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发表时间：
2003-03-01
期刊：
影响因子：
5.1
通讯作者：
Galipeau, J
中科院分区：
文献类型：
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作者：
Eliopoulos, N;Al-Khaldi, A;Galipeau, J
骨髓基质细胞(MSCs)是一种出生后的祖细胞，可以很容易地在体外大量培养，这一特点在细胞治疗应用中具有吸引力，基因工程MSCs可以作为一种自体细胞载体来输送治疗性蛋白。骨髓间充质干细胞在转基因细胞治疗中的有效性将取决于它们在非清髓、免疫功能良好的受者体内的植入潜力。此外，与静脉或腹膜内输注相比，皮下注射MSCs的能力将通过在临床环境中提供一种易于获取和可回收的人工皮下植入物来增强安全性。为了验证这一假设，对MSCs进行了逆转录病毒工程，使其分泌小鼠促红细胞生成素(EPO)，并在非清髓同基因小鼠中确定了它们的效果。当分泌EPO的MSCs作为“游离”细胞通过皮下或腹膜内注射时，在相同的细胞剂量下，导致显著但暂时的红细胞压积在55+/-13天内增加到70%以上。相比之下，在皮下植入Matriger植入MSCs的小鼠中，六只小鼠中有四只的红细胞压积保持在80%的水平超过110天(P<；0.05)。此外，混合在Matrigel中的分泌EPO的MSCs诱导并直接参与新生血管的形成，反映了其间充质可塑性。植入与人类相容的牛胶原基质中的MSCs也导致红细胞压积在75+/-8.9天内保持在70%。综上所述，植入基质的MSCs将自发形成一种新生血管的器官样物质，支持可溶性血浆蛋白直接释放到血液中，从而在非去髓移植的受者中发挥持续的药理作用。
Marrow stromal cells (MSCs) are postnatal progenitor cells that can be easily cultured ex vivo to large amounts, This feature is attractive for cell therapy applications where genetically engineered MSCs could serve as an autologous cellular vehicle for the delivery of therapeutic proteins. The usefulness of MSCs in transgenic cell therapy will rely upon their potential to engraft in nonmyeloablated, immunocompetent recipients. Further, the ability to deliver MSCs subcutaneously - as opposed to intravenous or intraperitoneal infusions - would enhance safety by providing an easily accessible, and retrievable, artificial subcutaneous implant in a clinical setting. To test this hypothesis, MSCs were retrovirally engineered to secrete mouse erythropoietin (Epo) and their effect was ascertained in nonmyeloablated syngeneic mice. Epo-secreting MSCs when administered as 'free' cells by subcutaneous or intraperitoneal injection, at the same cell dose, led to a significant - yet temporary hematocrit increase to over 70% for 55+/-13 days. In contrast, in mice implanted subcutaneously with Matriger embedded MSCs, the hematocrit persisted at levels > 80% for over 110 days in four of six mice (P < 0.05 logrank). Moreover, Epo-secreting MSCs mixed in Matrigel elicited and directly participated in blood vessel formation de novo reflecting their mesenchymal plasticity. MSCs embedded in human-compatible bovine collagen matrix also led to a hematocrit > 70% for 75+/-8.9 days. In conclusion, matrix-embedded MSCs will spontaneously form a neovascularized organoid that supports the release of a soluble plasma protein directly into the bloodstream for a sustained pharmacological effect in nonmyeloablated recipients.