Multi-function of adipose-derived stem cells on gut disorder: from bench to bedside

Abstract

Adipose-derived stem cells (ADSCs) are a specific type of mesenchymal stem cells (MSCs) obtained easily from adipose tissue (AT). Compared with MSCs, ADSCs are easier to obtain, have fewer ethical issues, and have a higher proliferative capacity, which makes them a promising type of stem cell in regenerative medicine. ADSCs possess impressive capabilities in cell regeneration as well as differentiation, making them promising candidates for injury repair, tissue regeneration and alleviation of inflamed tissues. At present, most clinical studies on ADSCs focus on the treatment of wounds, multiple sclerosis, soft tissue trauma, aging, diabetes, Parkinson’s disease, bone and cartilage regeneration, stroke, and spinal cord injury, while its clinical applications in the gastrointestinal tract are relatively few. Therefore, this review summarizes the findings of preclinical experiments, clinical trials, and areas that may require further development of ADSCs in the treatment of digestive disorders, including inflammatory bowel disease (IBD), colorectal cancer (CRC), colorectal fibrosis, hepatocellular carcinoma, hepatic fibrosis, gastric cancer (GC), gastrostomy closure and radiation-induced proctitis. The review is concluded by discussing the goals for improvement and future directions for ADSCs before large-scale clinical application.

Graphical Abstract:

Keywords: Adipose-derived stem cells; Anti-inflammation; Fibrosis; Immunoregulatory effects; Inflammatory bowel disease; Mesenchymal stem cells.

Fig. 1

Differences between ADSCs and other MSCs. MSCs derived from bone marrow, umbilical cord and AT are called BMSCs, UC-MSCs and ADSCs, respectively. ADSCs and other MSCs have different roles in proliferation ability, immunomodulatory function and clinical application

Fig. 2

Schema diagrams of isolation, acquisition, culture steps as well as differentiation of ADSCs. (A) The ADSC isolation protocol includes four main steps: harvesting, digestion, purification, and cell culture. (B) ADSCs can differentiate into several cell types including osteoblasts, adipocytes, chondrocytes, cardiomyocytes, endothelial cells, and neurons, via multiple signaling pathways

Fig. 3

Immune mechanisms of intestinal inflammation and immunomodulation of intestinal inflammation treated with ADSCs. (A) The immune systems activate during gut inflammation, with adaptive immunity showing increased Th cells and decreased Tregs, while innate immunity involves the activation and migration of innate immune cells, both contributing to inflammation and potential intestinal fibrosis. (B) ADSCs reduce intestinal inflammation and modulate immunity by decreasing Th cells and increasing Tregs, blocking Th proliferation, and promoting Tregs growth through anti-inflammatory factors. They also convert Mφs to anti-inflammatory types, mature DCs, reduce neutrophil recruitment and reduce cytotoxic effects of NK cells

Fig. 4

Pro-inflammatory and anti-inflammatory effects of NETs. (A) The REDD1/NETosis/IL-1β axis can activate intestinal inflammatory responses. Moreover, ANCA binds to the surface of neutrophils, activates neutrophils and promotes NETs release. (B) NETs can exert an anti-inflammatory effect. First, NETs can downregulate IL-6 and upregulate IL-10 secretion in LPS-activated Mφs in RA. Secondly, NETs can directly promote the reduction of inflammation by degrading cytokines and chemokines such as IL-1β, IL-6, MIP-1, and TNF via serine proteases in gout

Fig. 5

Underlying mechanism model of ADSCs in immune regulation, anti-inflammation and tissue repair in gastrointestinal tract. The immunomodulatory role of ADSCs is predominantly demonstrated through the promotion of Tregs, M2Mφs and immature DCs alongside the suppression of Th, M1Mφs, mature DCs, neutrophil and NK cells proliferation. ADSCs migrate to inflammatory sites and subsequently localize within the ECM, where they mediate anti-inflammatory effects through a three-step mechanistic cascade. Furthermore, the tissue repair capabilities of ADSCs are evident in their ability to restore endothelial cells through the release of various cytokines and EVs, while concurrently exhibiting certain anti-inflammatory properties

Fig. 6

Mode diagram of the role and mechanisms of ADSCs in the treatment of IBD, gastric disorders, CRC, and liver diseases. (A) In the treatment of IBD, ADSCs mainly exert their immunomodulatory function. However, ADSCs from IBD patients (P-ADSCs) may exert an immunosuppressive function that is inferior to that of ADSCs from healthy individuals (H-ADSCs). (B) ADSCs reduce ECM deposition in colorectal fibrosis by suppressing gene expression, inhibiting fibroblast activation, and promoting M2Mφ activation. In CRC, ADSCs can either promote or inhibit tumor development by regulating immune cell activity and inhibiting the Wnt pathway, or by secreting IL-6, Cyr61, and ANGPTL4. (C) ADSCs treat hepatic fibrosis by lecturing collagen fibers and differentiating into stem cells, while treating hepatocellular carcinoma by inhibiting oncogenic markers and metalloproteinases to reduce tumor migration. (D) In gastric cancer (GC), ADSCs can play either promoting or inhibiting roles equally. And the promotion of gastrectomy closure is mainly through the repair of fibrous and vascular tissues