Noninvasive Tracking and Regenerative Capabilities of Transplanted Human Umbilical Cord-Derived Mesenchymal Stem Cells Labeled with I-III-IV Semiconducting Nanocrystals in Liver-Injured Living Mice.

Abstract

Acute liver injury is a critical syndrome ascribed to prevalent death of hepatocytes and imperatively requires liver transplantation. Such a methodology is certainly hampered due to the deficit of healthy donors. In this regard, stem cell-based regenerative therapies are attractive in repairing injured tissues and organs for medical applications. However, it is crucial to understand the migration, engraftment, and regeneration capabilities of transplanted stem cells in the living animal models. For the first time, we demonstrate rapid labeling of umbilical cord-derived mesenchymal stem cells (MSCs) with near-infrared (NIR)-fluorescent CuInS2-ZnS nanocrystals (CIZS-NCs) to develop innovative nanobioconjugates (MSCs-CIZS-NBCs) that exhibit 98% labeling efficiency. Before nanobioconjugate synthesis, the pristine CIZS-NCs were prepared via a two-step, hot-injection, rapid and low-cost domestic-microwave-refluxing (MW-R) method within 6 min. The as-synthesized CIZS-NCs display high photoluminescence quantum yield (∼88%) and long-lived lifetime (23.4 μs). In contrast to unlabeled MSCs, the MSCs-CIZS nanobioconjugates show excellent biocompatibility without affecting the stemness, as confirmed by cell viability, immunophenotyping (CD44+, CD105+, CD90+), multi-lineage-specific gene expressions, and differentiation into adipocytes, osteocytes, and chondrocytes. The in vivo fluorescence tracking analyses revealed that the MSCs-CIZS-NBCs after tail-vein injection were initially trapped in the lungs and gradually engrafted in the injured liver within 2 h. The regeneration potential of MSCs-CIZS-NBCs was confirmed via renewal of the portal tract composed of portal veins, bile ducts, and hepatic arteries around the hepatocytes. Consequently, no apparent inflammations, necrosis, or apoptosis was observed in the acetaminophen (APAP)-induced liver-injured BALB/c mice model over 3 days after transplantation, as corroborated using laser-scanning confocal microscopy and histopathological and hematological analyses. Hence, our innovative NIR-fluorescent MSCs-CIZS-NBCs offer an off-the-self technology for noninvasive tracking of transplanted MSCs in an acute-liver-injured animal model for future image-guided cell-therapies.