Zhao Qingguo, Gregory Carl A, Lee Ryang Hwa, Reger Roxanne L, Qin Lizheng, Hai Bo, Park Min Sung, Yoon Nara, Clough Bret, McNeill Eoin, Prockop Darwin J, Liu Fei
Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine at Scott & White, Temple, TX 76502.
Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine at Scott & White, Temple, TX 76502
Proc Natl Acad Sci U S A. 2015 Jan 13;112(2):530-5. doi: 10.1073/pnas.1423008112. Epub 2014 Dec 29.
Mesenchymal stem or stromal cells (MSCs) have many potential therapeutic applications including therapies for cancers and tissue damages caused by cancers or radical cancer treatments. However, tissue-derived MSCs such as bone marrow MSCs (BM-MSCs) may promote cancer progression and have considerable donor variations and limited expandability. These issues hinder the potential applications of MSCs, especially those in cancer patients. To circumvent these issues, we derived MSCs from transgene-free human induced pluripotent stem cells (iPSCs) efficiently with a modified protocol that eliminated the need of flow cytometric sorting. Our iPSC-derived MSCs were readily expandable, but still underwent senescence after prolonged culture and did not form teratomas. These iPSC-derived MSCs homed to cancers with efficiencies similar to BM-MSCs but were much less prone than BM-MSCs to promote the epithelial-mesenchymal transition, invasion, stemness, and growth of cancer cells. The observations were probably explained by the much lower expression of receptors for interleukin-1 and TGFβ, downstream protumor factors, and hyaluronan and its cofactor TSG6, which all contribute to the protumor effects of BM-MSCs. The data suggest that iPSC-derived MSCs prepared with the modified protocol are a safer and better alternative to BM-MSCs for therapeutic applications in cancer patients. The protocol is scalable and can be used to prepare the large number of cells required for "off-the-shelf" therapies and bioengineering applications.
间充质干细胞（MSCs）具有许多潜在的治疗应用，包括针对癌症以及由癌症或根治性癌症治疗引起的组织损伤的治疗。然而，诸如骨髓间充质干细胞（BM-MSCs）等组织来源的间充质干细胞可能会促进癌症进展，并且存在相当大的供体差异以及有限的可扩展性。这些问题阻碍了间充质干细胞的潜在应用，尤其是在癌症患者中的应用。为了规避这些问题，我们采用一种改良方案从无转基因的人诱导多能干细胞（iPSCs）高效地衍生出间充质干细胞，该方案无需流式细胞术分选。我们的iPSC衍生的间充质干细胞易于扩增，但在长期培养后仍会衰老，且不会形成畸胎瘤。这些iPSC衍生的间充质干细胞归巢至癌症部位的效率与BM-MSCs相似，但比BM-MSCs更不易促进癌细胞的上皮-间质转化、侵袭、干性和生长。这些观察结果可能是由于白细胞介素-1和TGFβ的受体、下游促肿瘤因子以及透明质酸及其辅因子TSG6的表达低得多，而这些都有助于BM-MSCs的促肿瘤作用。数据表明，用改良方案制备的iPSC衍生的间充质干细胞是用于癌症患者治疗应用的比BM-MSCs更安全、更好的替代品。该方案具有可扩展性，可用于制备“现货”疗法和生物工程应用所需的大量细胞。
