Constructing a cell microenvironment with biomaterial scaffolds for stem cell therapy

Abstract

Stem cell therapy is widely recognized as a promising strategy for exerting therapeutic effects after injury in degenerative diseases. However, limitations such as low cell retention and survival rates after transplantation exist in clinical applications. In recent years, emerging biomaterials that provide a supportable cellular microenvironment for transplanted cells have optimized the therapeutic efficacy of stem cells in injured tissues or organs. Advances in the engineered microenvironment are revolutionizing our understanding of stem cell-based therapies by co-transplanting with synthetic and tissue-derived biomaterials, which offer a scaffold for stem cells and propose an unprecedented opportunity to further employ significant influences in tissue repair and regeneration.

Keywords: Biomaterials; Cellular therapy; Engineered microenvironment; Scaffold; Stem cells; Tissue regeneration.

Fig. 1

Engineered microenvironment for stem cell therapy. Low cell retention and engraftment exist in vivo transplantation of stem cells. To address these challenges, biochemical or biophysical modifications of biomaterials are urgently needed to establish a favorable microenvironment for stem cell therapy. By means of engineered bioactive scaffolds, a suitable niche was designed to trigger specification events of stem cell fate specification events, enhancing cell differentiation, retention, engraftment, and self-renewal in vivo via cell–matrix or cell–cell interaction, and thus promoting tissue repair and regeneration

Fig. 2

Strategies for artificial scaffolds for cell enhancement. Engineered biomaterials based on their biochemical and biophysical microenvironment, for example, the characteristics of biophysical cues of surface topography, material shape and size, and mechanical forces, as well as biochemical cues to conjugate growth factors, controlling to release specific small molecules and tissue-derived ECM scaffold, were extensively applied in stem cell-based therapy to improve cell maintenance in vitro and in vivo. Strategies designed to regulate cell behavior play an important role in enhancing therapeutic effects after transplantation in vivo

Fig. 3

Incorporation of PGE₂ into the CS hydrogel created a balanced microenvironment in vivo. Inflammation, tissue regeneration, and remodeling are three important phases in wound healing events at the injured site. In this study, the increased anti-inflammatory and pro-angiogenic activities of macrophages and the reduction of fibrosis were investigated, which demonstrated that the wound microenvironment was better improved by hydrogel in vivo, exhibiting a balanced niche of the overlapping inflammatory, regenerative (angiogenesis) and remodeling (fibrosis) phases of cutaneous wound healing. Reprinted with permission from [79]

Fig. 4

The engineering approach provides a niche for stem cell transplantation. A biomaterial designed with growth factors was applied for stem cell transplantation, for example, human placenta-derived MSCs (hP-MSCs) applied to treat trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice [104]. First, stem cells were cultured in CS-IGF-1C hydrogels in vitro, stimulating the production of PGE₂, and then upregulating the cell proliferation markers of EGF, IGF-1, and HGF. Second, stem cells were co-transplanted with the hydrogel in vivo and PGE₂ released from stem cell uptake through binding to its receptor in macrophages. Down-regulated genes of IL-1β, IFN-γ, IL-6, and TNF-α were observed and the secretion of IL-10 by M2 macrophages, promoting the polarization of M2 macrophages in colitis of the mouse model. Finally, the results determined the functional recovery of colitis mice under the stem cell co-transplantation system of stem cells with conjugated growth factors

Fig. 5

Controlled release of small molecules, growth factors, and proteins. Control release systems can be considered an effective way to modulate stem cell behavior. a The utilization of NO-releasing hydrogels to support stem cell delivery through the control of NO generation can upregulate the expression of endothelial cell-like phenotypes, such as VEGFA, bFGF, ANG1, ANG2, and then significantly facilitate neovascularization in mouse with ischemic hindlimb [109]; b Injectable GMs were employed to deliver growth factors and as vehicles of stem cells, which can promote cell differentiation into nucleus pulposus (NP)-like gene markers of COL2, ACAN, Krt19, CD24, determining a promising approach for the in vivo treatment of rat degenerative disc disease [111]; c The PLGA and SL deliver system were designed to control the release of BMP-2, and then applied the platform to build a suitable microenvironment for stem cell culture. In this culture system, stem cell matrix mineralization abilities were detected, and osteogenic cell-related gene expression of COL-1, OCN, OPN, and RUNX2 was demonstrated, indicating the potential of the engineered platform for bone tissue regeneration [110]