Exploitation of fibrin-based signaling niche for deriving progenitors from human adipose-derived mesenchymal stem cells towards potential neural engineering applications

Krishnapriya Chandrababu,Lissy K Krishnan,Manesh Senan

doi:10.1038/s41598-020-63445-2

Abstract

Adipose-derived mesenchymal stem cells (hADMSC) retaining proliferation and multi-differentiation potential may support the central nervous system (CNS) regeneration. Multipotency of MSC may result in both desirable and undesirable cells, post-transplantation. A better strategy to attain desired cells may be in vitro commitment of hADMSCs to uni-/bi- potent neural progenitor cells (NPCs), prior to transplantation. Derivation of stable NPCs may require a suitable niche eliciting proliferation and differentiation signals. The present study designed a biomimetic niche comprising insoluble fibrin supported adhesion matrix and exogenously added growth factors (GFs) for deriving different neural cells and established the role of Notch and Wnt signals for proliferation and differentiation of hADMSCs, respectively. The stable transformation of hADMSCs into neurospheres (NS) comprising Nestin+ve NPCs was achieved consistently. Slight modifications of niche enable differentiation of NS to NPCs; NPCs to neurons; NPCs to oligodendrocyte progenitor cells (OPCs); and OPCs to oligodendrocytes (OLG). Fibrin plays a crucial role in the conversion of hADMSC to NS and NPCs to OPCs; but, not essential for OPC to OLG maturation. Co-survival and cell-cell interaction of NPC derived neurons and OPCs promoting OLG maturation is illustrated. The designed biomimetic niche shows the potential for directing autologous ADMSCs to neural cells for applications in regenerative medicine.

Highlights

Adipose-derived mesenchymal stem cells retaining proliferation and multi-differentiation potential may support the central nervous system (CNS) regeneration
The tri-lineage differentiation potential and classical MSC surface marker expressions are in accordance with the standards recommended by the International Society for Cellular Therapy (ISCT)
The multipotency of human adipose-derived mesenchymal stem cells (hADMSC) facilitates the derivation of different functional cells for regenerative applications

Summary

Introduction

Adipose-derived mesenchymal stem cells (hADMSC) retaining proliferation and multi-differentiation potential may support the central nervous system (CNS) regeneration. The present study designed a biomimetic niche comprising insoluble fibrin supported adhesion matrix and exogenously added growth factors (GFs) for deriving different neural cells and established the role of Notch and Wnt signals for proliferation and differentiation of hADMSCs, respectively. The injured central nervous system (CNS) tissue shows limited and slothful ability to regenerate This may be because of the inadequate number of endogenous neural progenitor cells (NPC) and the development of unfavorable micro-environment post-injury, affecting cell homing and differentiation. Various in vitro studies established that the fibrin-based niche is efficient in promoting differentiation and proliferation of stem/progenitor cells to neurons, keratinocytes or endothelial cells[5,7,8,9]. This study attempted cell-specific modification of fibrin-based niche to obtain stage-wise and stable differentiation of hADMSCs to both neural and glial cells. The differentiation potential of NPCs to oligodendrocytes and neurons were established using multiple markers

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Results

Conclusion