Human mesenchymal stem cells self-renew and differentiate according to a deterministic hierarchy

Area of Science:

• Stem Cell Biology
• Regenerative Medicine
• Tissue Engineering

Background:

• Mesenchymal progenitor cells (MPCs) are often termed mesenchymal stem cells (MSCs).
• The definition of stem cells requires robust self-renewal and multilineage differentiation.
• Current data on MSC self-renewal from single-cell clones is limited.

Purpose of the Study:

• To investigate the self-renewal and differentiation potential of human umbilical cord perivascular cells (HUCPVCs).
• To establish a hierarchical model for mesenchymal stem cell (MSC) self-renewal and differentiation.

Main Methods:

• Isolation and in vitro multilineage differentiation of HUCPVCs.
• In vivo assessment of HUCPVCs in connective tissue healing.
• Isolation of single-cell-derived (SCD) parent and daughter clones using Y-chromosome fluorescent in situ hybridization.

Main Results:

• HUCPVCs exhibited multilineage differentiation capacity in vitro.
• HUCPVCs promoted rapid connective tissue healing in vivo, generating bone, cartilage, and fibrous stroma.
• High clonogenic frequency of HUCPVCs enabled isolation of definitive SCD clones.

Conclusions:

• A new hierarchical schema for MSC self-renewal and differentiation was formulated.
• Self-renewing multipotent MSCs give rise to progressively restricted progenitors.
• Progenitors gradually lose differentiation potential, ultimately restricting to a fibroblast lineage.