Niche-Dependent Regulations of Metabolic Balance in High-Fat Diet–Induced Diabetic Mice by Mesenchymal Stromal Cells

Abstract

Mesenchymal stromal cells (MSCs) have great potential to maintain glucose homeostasis and metabolic balance. Here, we demonstrate that in mice continuously fed with high-fat diet (HFD) that developed non-insulindependent diabetes, two episodes of systemic MSC transplantations effectively improve glucose tolerance and blood glucose homeostasis and reduce body weight through targeting pancreas and insulin-sensitive tissues and organs via site-specific mechanisms. MSCs support pancreatic islet growth by direct differentiation into insulin-producing cells and by mitigating the cytotoxicity of interleukin 1 (IL-1) and tumor necrosis factor-a (TNF-a) in the pancreas. Localization of MSCs in the liver and skeletal muscles in diabetic animals is also enhanced and therefore improves glucose tolerance, although long-term engraftment is not observed. MSCs prevent HFD-induced fatty liver development and restore glycogen storage in hepatocytes. Increased expression of IL-1 receptor antagonist and Glut4 in skeletal muscles after MSC transplantation results in better blood glucose homeostasis. Intriguingly, systemic MSC transplantation does not alter adipocyte number, but it decreases HFD-induced cell infiltration in adipose tissues and reduces serum levels of adipokines, including leptin and TNF-a. Taken together, systemic MSC transplantation ameliorates HFD-induced obesity and restores metabolic balance through multisystemic regulations that are niche dependent. Such findings have supported systemic transplantation of MSCs to correct metabolic imbalance.Impairment of glucose tolerance and insulin resistance initiates type 2 diabetes; however, exhaustion of the insulin supply due to b-cell apoptosis is the ultimate pathomechanism of both type 1 and 2 diabetes (1,2). The liver, adipose tissues, skeletal muscles, and vascular tissues are insulin-sensitive tissues responsible for blood glucose homeostasis (1,3). Inflammation adversely affects insulin sensitivity and worsens diabetic retinopathies, neuropathies, and vasculopathies (4-6). Proinflammatory cytokines produced by macrophages, such as tumor necrosis factor-a (TNF-a) and interleukin 1 (IL-1), create a vicious cycle of reduced insulin sensitivity (3,(7)(8)(9).To the present, more than 300 clinical trials of mesenchymal stem/stromal cell (MSC) transplantations have been conducted worldwide with a wide clinical application targeting more than 50 indications (www.clinicaltrials.gov). Systemic transplantation is the most favorable route for MSC delivery from a safety and systemic regulation point of view, and 56% of MSC clinical trials are allogenic transplantation (10). It is well accepted that the majority of MSCs are initially distributed in vital organs (11-16) and are also frequently found in tissues of mesenchymal origin (11,12) when systemically administered. Nevertheless, the long-term engraftment of MSCs is minimal, and the engraftment rate is not correlated with therapeutic response in human studies (17). The acutely diseased and damaged tissues show increased loca...

Mesenchymal stem cells prolong survival and prevent lethal complications in a porcine model of fulminant liver failure

“…Paracrine tissue support and immunomodulation by MSCs are imperative during acute tissue injury, and these occur in a tissue‐specific manner in vivo . Liver regeneration involves numerous tissue growth factors and cytokines .…”

“…Paracrine tissue support and immunomodulation by MSCs are imperative during acute tissue injury, and these occur in a tissuespecific manner in vivo. 25,[57][58][59] Liver regeneration involves numerous tissue growth factors and cytokines. [48][49][50][51]60,61 HGF triggers hepatocyte proliferation and guides hepatic progenitor-cell differentiation into hepatocytes.…”

Assessment of three fasting plasma glucose targets for insulin glargine-based therapy in people with type 2 diabetes mellitus in China: study protocol for a randomized controlled trial

“…Although Chinese physicians are familiar with Chinese Diabetes Society guideline recommendations for the management of T2DM, evidence shows that many Chinese T2DM patients have poor glycemic control [6, 27, 28]. A possible reason for this is the overly cautious approach to insulin initiation and titration, which, in turn, is thought to be a result of physician anxiety about invoking events of hypoglycemia in patients.…”

“…In China, the impact of T2DM is particularly disconcerting: the Chinese T2DM population is nearing 100 million individuals—about a quarter of the global T2DM population—and is projected to reach 142.7 million by 2035 [3–5]. Moreover, recent data suggest that, in general, patients with T2DM in China have poor glycemic control; a large observational study conducted at 209 hospitals across China found that patients had a mean hemoglobin A1c (HbA1c) level of 9.6 ± 2.0 % before initiation of basal insulin [6], and it has been reported that only 35.9 % of Chinese T2DM patients who are treated exclusively with oral antidiabetic drugs (OADs) achieve HbA1c levels of <7 % [7]. …”

Lixisenatide Improves Glycemic Control in Asian Type 2 Diabetic Patients Inadequately Controlled With Oral Antidiabetic Drugs: An Individual Patient Data Meta-Analysis

“…Currently in East Asia, patients with T2DM are commonly prescribed metformin/sulfonylurea, and the initiation of insulin therapy is often delayed [4, 5]. Because inadequately controlled T2DM can give rise to serious, irreversible medical complications, there is thus an urgent need to identify alternative treatment strategies that would improve glycemic control in the East Asian T2DM population.…”