Enhanced hepatogenic differentiation of bone marrow derived mesenchymal stem cells on liver ECM hydrogel

Abstract

Bone marrow derived mesenchymal stem cells (BM-MSC) is a promising alternative cell source to primary hepatocytes because of their ability to differentiate into hepatocyte-like cells. However, their inability to differentiate efficiently and potential to turn into myofibroblasts restrict their applications. This study developed a plate coating from the liver extracellular matrix (ECM) and investigated its ability in facilitating the BM-MSCs proliferation, hepatic differentiation, and hepatocyte-specific functions during in vitro culture. After 28-day culture, BM-MSCs on the ECM coating showed hepatocyte-like morphology, and certain cells took up low-density lipoprotein. Synthesis of albumin, urea, and anti-alpha-fetoprotein, as well as expression of certain hepatic markers, in cells cultured on ECM were higher than cells cultured on non-coated and Matrigel-coated plates. mRNA levels of CYP3A4, albumin, CK18, and CYP7A1 in cells on ECM coating were significantly higher than cells cultured on the non-coating environment. In conclusion, viability and hepatogenic differentiation of BM-MSCs cultured on both Matrigel and ECM coating were significantly enhanced compared with those cultured on non-coated plates. Moreover, the liver ECM coating induced additional metabolic functions relative to the Matrigel coating. The liver ECM hydrogel preserves the natural composition, promotes simple gelling, induces efficient stem cell hepatogenic differentiation, and may have uses as an injectable intermedium for hepatocytes. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 829-838, 2018.

Imaging-Based Screen Identifies Laminin 411 as a Physiologically Relevant Niche Factor with Importance for i-Hep Applications

“…Extracellular signals delivered via a complex 3-dimensional protein-rich environment termed the “niche” tightly regulate hepatocyte function ( Orford and Scadden, 2008 , Morrison and Spradling, 2008 ). Recent attempts at enhancing the function of hepatocytes derived from iPSCs (i-Heps) by targeting the niche ( Shan et al., 2013 , Wang et al., 2017 ), though promising, are still unable to bridge the gap in functionality. One of the major reasons for this failure is the lack of a systematic approach to empirically define a signature of maturity that must be crossed in order for i-Heps to become suitably useful.…”

In�vitro differentiation of rhesus macaque bone marrow‑ and adipose tissue‑derived MSCs into hepatocyte‑like cells

“…The typical functional assays for hepatocyte identification are glycogen deposition, urea production, albumin secretion and low-density lipoprotein uptake assays. In addition, hepatocyte-related gene expression is widely used in the detection of MSCs differentiating into HLCs (39)(40)(41). In the present study, HLCs differentiated from both BM-MSCs and AT-MSCs acquired the functions of glycogen deposition, urea secretion and expression of hepatocyte-related genes (including CK-18, HNF-4α, ALB, CYP3A4 and CYP7A1) in the differentiation process.…”

Decellularized extracellular matrix‐rich hydrogel–silver nanoparticle mixture as a potential treatment for acute liver failure model

“…The ECM powder was digested by agitation until LECM digest become clear. The digest was then neutralized by NaOH (1 N) until it reached pH 7–8 and then diluted with PBS to a final concentration of 5 mg/ml (Wang, Li, Dean, Mishra, & Wekesa, 2018).…”