Human Fetal Bone Marrow-Derived Mesenchymal Stem Cells Promote the Proliferation and Differentiation of Pancreatic Progenitor Cells and the Engraftment Function of Islet-Like Cell Clusters

Xing Yu Li,Po Sing Leung,Shang Ying Wu

doi:10.3390/ijms20174083

Abstract

Pancreatic progenitor cells (PPCs) are the primary source for all pancreatic cells, including beta-cells, and thus the proliferation and differentiation of PPCs into islet-like cell clusters (ICCs) opens an avenue to providing transplantable islets for diabetic patients. Meanwhile, mesenchymal stem cells (MSCs) can enhance the development and function of different cell types of interest, but their role on PPCs remains unknown. We aimed to explore the mechanism-of-action whereby MSCs induce the in vitro and in vivo PPC/ICC development by means of our established co-culture system of human PPCs with human fetal bone marrow-derived MSCs. We examined the effect of MSC-conditioned medium on PPC proliferation and survival. Meanwhile, we studied the effect of MSC co-culture enhanced PPC/ICC function in vitro and in vivo co-/transplantation. Furthermore, we identified IGF1 as a critical factor responsible for the MSC effects on PPC differentiation and proliferation via IGF1-PI3K/Akt and IGF1-MEK/ERK1/2, respectively. In conclusion, our data indicate that MSCs stimulated the differentiation and proliferation of human PPCs via IGF1 signaling, and more importantly, promoted the in vivo engraftment function of ICCs. Taken together, our protocol may provide a mechanism-driven basis for the proliferation and differentiation of PPCs into clinically transplantable islets.

Highlights

Diabetes mellitus (DM) is an endocrine disease with chronic complications, which are primarily characterized with insulin-deficiency because of pancreatic beta-cell loss
We examined the levels of proliferation and cell death of pancreatic progenitor cells (PPCs) treated with mesenchymal stem cells (MSCs)-conditioned medium as well as employed an IGF1 receptor (IGF1R) inhibitor—picropodophyllin (PPP)—to verify the proposed pathways of Insulin-like growth factor 1 (IGF1)-PI3K/Akt and MEK/ERK1/2 involved
Recent repoIrttshhasavbeeesnhorwecnogthnaizt erdattmhaetstehnechmyemseenacchtys mone bisocthrituicpasltrfeoarminavnivdodpoawnncsrteraesamforomf aNtgionn3 [t2o6d].irReecctetnhte rleinpeoargtse hoaf vpeanschroewatnictβh-acterllaftamtee[s2e7n].chInymligehatcotfstohnisbkontohwulpedstgree,awmeaanimd eddowtonusttirleizaemthoefnNicghne3otfohduimreacnt the lineage of pancreatic β-cell fate [27]. In light of this knowledge, we aimed to utilize the niche of human MSCs, mimicking an in vitro microenvironment to promote the development of human PPCs into islet-like cell clusters (ICCs) with transplantation potential

Summary

Introduction

Diabetes mellitus (DM) is an endocrine disease with chronic complications, which are primarily characterized with insulin-deficiency because of pancreatic beta-cell loss. Life-long insulin injection leads to complicated side effects, notably hypoglycemia. In view of this fact, patients need to regain their physiological insulin secretion in response to glucose rather than using insulin therapy alone [3]. Islet transplantation is a curable option for the patients with insulin-dependent diabetes mellitus. Pancreatic stem cells are the source of all pancreatic cells and can differentiate into insulin-producing islet-like cell clusters, without processing complicated stages of embryonic development [4]. Enhancement for the proliferation and differentiation of pancreatic progenitor cells (PPCs) provides numerous sources and potential alternatives of islets

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Conclusion