John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138.
Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138.
Proc Natl Acad Sci U S A. 2019 Jul 30;116(31):15392-15397. doi: 10.1073/pnas.1819415116. Epub 2019 Jul 16.
Mesenchymal stem cell (MSC) therapies demonstrate particular promise in ameliorating diseases of immune dysregulation but are hampered by short in vivo cell persistence and inconsistencies in phenotype. Here, we demonstrate that biomaterial encapsulation into alginate using a microfluidic device could substantially increase in vivo MSC persistence after intravenous (i.v.) injection. A combination of cell cluster formation and subsequent cross-linking with polylysine led to an increase in injected MSC half-life by more than an order of magnitude. These modifications extended persistence even in the presence of innate and adaptive immunity-mediated clearance. Licensing of encapsulated MSCs with inflammatory cytokine pretransplantation increased expression of immunomodulatory-associated genes, and licensed encapsulates promoted repopulation of recipient blood and bone marrow with allogeneic donor cells after sublethal irradiation by a ∼2-fold increase. The ability of microgel encapsulation to sustain MSC survival and increase overall immunomodulatory capacity may be applicable for improving MSC therapies in general.
间充质干细胞（MSC）疗法在改善免疫失调疾病方面具有特殊的应用前景，但由于其在体内的细胞持续时间短和表型不一致，该疗法受到限制。在这里，我们证明了使用微流控设备将生物材料包封到藻酸盐中可以显著增加静脉内（i.v.）注射后 MSC 在体内的持续时间。细胞团的形成和随后用聚赖氨酸交联导致注射的 MSC 半衰期增加了一个数量级以上。这些修饰甚至在先天和适应性免疫介导的清除存在的情况下也延长了其持续时间。在移植前用炎性细胞因子对包封的 MSC 进行许可处理会增加免疫调节相关基因的表达，并且许可的包封物可促进同种异体供体细胞在亚致死照射后重新填充受者血液和骨髓，其数量增加了约 2 倍。微凝胶包封维持 MSC 存活和提高整体免疫调节能力的能力可能适用于一般的 MSC 治疗。
