Effect of Composition of Lung Biomimetic Niche on the Mesenchymal Stem Cell Differentiation toward Alveolar Type II Pneumocytes

Abstract

Pulmonary niche dynamically orchestrates the signals, such as proliferation or differentiation of mesenchymal stem cells (MSCs), which allows inducing tissue repair. Lung niche includes extracellular matrix (ECM), comprising hyaluronic acid (HA) and collagen (COLL), and several types of MSCs. Impaired ECM, in lung pathologies, makes the promising therapies based on MSCs ineffective, as it results in a reduced attachment and homing of MSCs, precluding their differentiation and viability. To overcome this problem, in this study a pulmonary biomimetic niche based on HA and COLL hydrogel is developed, with the specific aim to elucidate the role of COLL and HA/COLL semi-interpenetrating polymer networks (SIPNs) in directing the differentiation of MSCs into Alveolar Type II (ATII) cells. The effect of low (L), medium (M), and high (H) molecular weight (MW) HA is investigated, both like structural component of the SIPNs hydrogel and like trophic factor in cell culture media solution. HA in the culture media significantly improves surfactant protein (SP)-C expression (≈2 ng mL −1 ), without showing difference in the MW tested, compared to control only (≈1 ng mL −1 ). Furthermore, LMWHA/COLL hydrogel promotes the SPC expression (approximately two times) compared to COLL, MMWHA/COLL, and HMWHA/COLL hydrogels.

Collagen–Mesenchymal Stem Cell Microspheres Embedded in Hyaluronic Acid Solutions as Biphasic Stem Niche Delivery Systems for Pulmonary Differentiation

“…The primary function of HA in the pulmonary ECM is to regulate water in the interstitium and stabilize surfactant proteins on the surface of the alveoli. Beyond this structural role, HA, depending on its MW, through its selective tropism for the CD44 receptor, appears to perform a great variety of biological activities. , It has been reported that LMW HA directly triggers CD44 signal transduction. It appears that lung tissue remodeling involves the CD44 receptor .…”

“…Accordingly, it was possible to quantitatively observe by an ELISA test that both SAGM and SAGM/HA containing mCOLLs attained an increase in expression compared to the DMEM control. Remarkably, the addition of HA, a physiological constituent of the pulmonary niche, to the SAGM solution amplified the amount of expression obtained by the use of SAGM medium alone. ,, In particular, the SPC expression was twice (about 4 ng/mL) that of the use of SAGM alone (about 2 ng/mL), with a high significance ( p -value < 0.0001). The primary function of HA in the pulmonary ECM is to regulate water in the interstitium and stabilize surfactant proteins on the surface of the alveoli.…”

“…Previous studies from our group demonstrated that MSCs embedded in a three-dimensional (3D) COLL matrix and incubated with lung media implemented by HA at different MWs (low, medium, and high) improve differentiation in ATII cells with a considerable increase in surfactant protein expression without finding a dependence on the HA MW used . However, it has been demonstrated in preclinical studies in mice that HA MW in a size range of about 67–215 kDa showed longer persistence in the lungs.…”