Injectable bone marrow microniches by co-culture of HSPCs with MSCs in 3D microscaffolds promote hematopoietic reconstitution from acute lethal radiation

Hematopoietic syndrome of acute radiation syndrome(h-ARS)is an acute illness resulted from the damage of bone marrow(BM)microenvironment after exposure to radiation.Currently,the clinical management of h-ARS is limited to medication-assisted treatment,while there is still no specific therapy for the hematopoietic injury from high-dose radiation exposure.Our study aimed to assemble biomimetic three-dimensional(3D)BM microniches by co-culture of hematopoietic stem and progenitor cells(HSPCs)and mesenchymal stem cells(MSCs)in porous,injectable and viscoelastic microscaffolds in vitro.The biodegradable BM microniches were then transplanted in vivo into the BM cavity for the treatment of h-ARS.We demonstrated that the maintenance of HSPCs was prolonged by co-culture with MSCs in the porous 3D microscaffolds with 84μm in pore diameter and 11.2 kPa in Young’s modulus compared with 2D co-culture system.Besides,the minimal effective dose and therapeutic effects of the BM microniches were investigated on a murine model of h-ARS,which showed that the intramedullary cavity-injected BM microniches could adequately promote hematopoietic reconstitution and mitigate death from acute lethal radiation with a dose as low as 1000 HSPCs.Furthermore,the mRNA expression of Notch1 and its downstream target gene Hes1 of HSPCs were increased when co-cultured with MSCs,while the Jagged1 expression of the co-cultured MSCs was upregulated,indicating the significance of Notch signaling pathway in maintenance of HSPCs.Collectively,our findings provide evidence that biomimetic and injectable 3D BM microniches could maintain HSPCs,promote hematopoiesis regeneration and alleviate post-radiation injury,which provides a promising approach to renovate conventional HSPCs transplantation for clinical treatment of blood and immune disorders.

Recruitment of endogenous progenitor cells by erythropoietin loaded particles for in situ cartilage regeneration

Cartilage injury affects millions of people throughout the world,and at this time there is no cure.While transplantation of stem cells has shown some success in the treatment of injured cartilage,such treatment is limited by limited cell sources and safety concerns.To overcome these drawbacks,a microscaffolds system was developed capable of targeting,reducing the inflammatory response and recruiting endogenous progenitor cells to cartilage-defect.Erythropoietin(EPO)-loaded-hyaluronic acid(HA)microscaffolds(HA+EPO)were fabricated and characterized.HA-microscaffolds showed good cell-compatibility and could target chondrocytes via CD44 receptors.HA+EPO was designed to slowly release EPO while recruiting progenitor cells.Finally,the ability of HA+EPO to repair cartilage-defects was assessed using a rabbit model of full-thickness cartilagedefect.Our results showed that the intra-articular administration of EPO,HA,and EPO+HA reduced the number of inflammatory cells inside the synovial-fluid,while EPO+HA had the greatest anti-inflammatory effects.Furthermore,among all groups,EPO+HA achieved the greatest progenitor cell recruitment and subsequent chondrogenesis.The results of this work support that,by targeting and localizing the release of growthfactors,HA+EPO can reduce inflammatory responses and promote progenitor cells responses.This new platform represents an alternative treatment to stem-cell transplantation for the treatment of cartilage injury.