Mesenchymal stem cells expressing insulin-like growth factor-I (MSC IGF) promote fracture healing and restore new bone formation in irs1 knockout mice

Analyses of MSC IGF autocrine and paracrine regenerative effects

Froilán Granero-Moltó, Timothy J. Myers, Jared A. Weis, Lara Longobardi, Li Tieshi, Yun Yan, Natasha Case, Janet Rubin, Anna Spagnoli

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Failures of fracture repair (nonunions) occur in 10% of all fractures. The use of mesenchymal stem cells (MSC) in tissue regeneration appears to be rationale, safe, and feasible. The contributions of MSC to the reparative process can occur through autocrine and paracrine effects. The primary objective of this study is to find a novel mean, by transplanting primary cultures of bone marrow-derived MSCs expressing insulin-like growth factor-I (MSC IGF), to promote these seed-and-soil actions of MSC to fully implement their regenerative abilities in fracture repair and nonunions. MSC IGF or traceable MSC IGF-Lac-Z were transplanted into wild-type or insulin-receptor-substrate knockout (Irs1 -/-) mice with a stabilized tibia fracture. Healing was assessed using biomechanical testing, microcomputed tomography (μCT), and histological analyses. We found that systemically transplanted MSC IGF through autocrine and paracrine actions improved the fracture mechanical strength and increased new bone content while accelerating mineralization. We determined that IGF-I adapted the response of transplanted MSC IGF to promote their differentiation into osteoblasts. In vitro and in vivo studies showed that IGF-I-induced osteoglastogenesis in MSCs was dependent of an intact IRS1-PI3K signaling. Furthermore, using Irs1 -/-mice as a nonunion fracture model through altered IGF signaling, we demonstrated that the autocrine effect of IGF-I on MSC restored the fracture new bone formation and promoted the occurrence of a well-organized callus that bridged the gap. A callus that was basically absent in Irs1 -/- left untransplanted or transplanted with MSCs. We provided evidence of effects and mechanisms for transplanted MSC IGF in fracture repair and potentially to treat nonunions.

Original languageEnglish (US)
Pages (from-to)1537-1548
Number of pages12
JournalSTEM CELLS
Volume29
Issue number10
DOIs
StatePublished - Oct 1 2011

Fingerprint

Fracture Healing
Mesenchymal Stromal Cells
Insulin-Like Growth Factor I
Osteogenesis
Knockout Mice
Bony Callus
Autocrine Communication
X-Ray Microtomography
Insulin Receptor
Osteoblasts
Tibia
Phosphatidylinositol 3-Kinases
Regeneration
Seeds
Soil
Bone Marrow
Bone and Bones

Keywords

  • Fracture healing
  • Insulin-like growth factor
  • Mesenchymal stem cells
  • Mouse models

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Cite this

Mesenchymal stem cells expressing insulin-like growth factor-I (MSC IGF) promote fracture healing and restore new bone formation in irs1 knockout mice : Analyses of MSC IGF autocrine and paracrine regenerative effects. / Granero-Moltó, Froilán; Myers, Timothy J.; Weis, Jared A.; Longobardi, Lara; Tieshi, Li; Yan, Yun; Case, Natasha; Rubin, Janet; Spagnoli, Anna.

In: STEM CELLS, Vol. 29, No. 10, 01.10.2011, p. 1537-1548.

Research output: Contribution to journalArticle

Granero-Moltó, Froilán ; Myers, Timothy J. ; Weis, Jared A. ; Longobardi, Lara ; Tieshi, Li ; Yan, Yun ; Case, Natasha ; Rubin, Janet ; Spagnoli, Anna. / Mesenchymal stem cells expressing insulin-like growth factor-I (MSC IGF) promote fracture healing and restore new bone formation in irs1 knockout mice : Analyses of MSC IGF autocrine and paracrine regenerative effects. In: STEM CELLS. 2011 ; Vol. 29, No. 10. pp. 1537-1548.
@article{0c72c11ad8ce419490991824242e4854,
title = "Mesenchymal stem cells expressing insulin-like growth factor-I (MSC IGF) promote fracture healing and restore new bone formation in irs1 knockout mice: Analyses of MSC IGF autocrine and paracrine regenerative effects",
abstract = "Failures of fracture repair (nonunions) occur in 10{\%} of all fractures. The use of mesenchymal stem cells (MSC) in tissue regeneration appears to be rationale, safe, and feasible. The contributions of MSC to the reparative process can occur through autocrine and paracrine effects. The primary objective of this study is to find a novel mean, by transplanting primary cultures of bone marrow-derived MSCs expressing insulin-like growth factor-I (MSC IGF), to promote these seed-and-soil actions of MSC to fully implement their regenerative abilities in fracture repair and nonunions. MSC IGF or traceable MSC IGF-Lac-Z were transplanted into wild-type or insulin-receptor-substrate knockout (Irs1 -/-) mice with a stabilized tibia fracture. Healing was assessed using biomechanical testing, microcomputed tomography (μCT), and histological analyses. We found that systemically transplanted MSC IGF through autocrine and paracrine actions improved the fracture mechanical strength and increased new bone content while accelerating mineralization. We determined that IGF-I adapted the response of transplanted MSC IGF to promote their differentiation into osteoblasts. In vitro and in vivo studies showed that IGF-I-induced osteoglastogenesis in MSCs was dependent of an intact IRS1-PI3K signaling. Furthermore, using Irs1 -/-mice as a nonunion fracture model through altered IGF signaling, we demonstrated that the autocrine effect of IGF-I on MSC restored the fracture new bone formation and promoted the occurrence of a well-organized callus that bridged the gap. A callus that was basically absent in Irs1 -/- left untransplanted or transplanted with MSCs. We provided evidence of effects and mechanisms for transplanted MSC IGF in fracture repair and potentially to treat nonunions.",
keywords = "Fracture healing, Insulin-like growth factor, Mesenchymal stem cells, Mouse models",
author = "Froil{\'a}n Granero-Molt{\'o} and Myers, {Timothy J.} and Weis, {Jared A.} and Lara Longobardi and Li Tieshi and Yun Yan and Natasha Case and Janet Rubin and Anna Spagnoli",
year = "2011",
month = "10",
day = "1",
doi = "10.1002/stem.697",
language = "English (US)",
volume = "29",
pages = "1537--1548",
journal = "Stem Cells",
issn = "1066-5099",
publisher = "AlphaMed Press",
number = "10",

}

TY - JOUR

T1 - Mesenchymal stem cells expressing insulin-like growth factor-I (MSC IGF) promote fracture healing and restore new bone formation in irs1 knockout mice

T2 - Analyses of MSC IGF autocrine and paracrine regenerative effects

AU - Granero-Moltó, Froilán

AU - Myers, Timothy J.

AU - Weis, Jared A.

AU - Longobardi, Lara

AU - Tieshi, Li

AU - Yan, Yun

AU - Case, Natasha

AU - Rubin, Janet

AU - Spagnoli, Anna

PY - 2011/10/1

Y1 - 2011/10/1

N2 - Failures of fracture repair (nonunions) occur in 10% of all fractures. The use of mesenchymal stem cells (MSC) in tissue regeneration appears to be rationale, safe, and feasible. The contributions of MSC to the reparative process can occur through autocrine and paracrine effects. The primary objective of this study is to find a novel mean, by transplanting primary cultures of bone marrow-derived MSCs expressing insulin-like growth factor-I (MSC IGF), to promote these seed-and-soil actions of MSC to fully implement their regenerative abilities in fracture repair and nonunions. MSC IGF or traceable MSC IGF-Lac-Z were transplanted into wild-type or insulin-receptor-substrate knockout (Irs1 -/-) mice with a stabilized tibia fracture. Healing was assessed using biomechanical testing, microcomputed tomography (μCT), and histological analyses. We found that systemically transplanted MSC IGF through autocrine and paracrine actions improved the fracture mechanical strength and increased new bone content while accelerating mineralization. We determined that IGF-I adapted the response of transplanted MSC IGF to promote their differentiation into osteoblasts. In vitro and in vivo studies showed that IGF-I-induced osteoglastogenesis in MSCs was dependent of an intact IRS1-PI3K signaling. Furthermore, using Irs1 -/-mice as a nonunion fracture model through altered IGF signaling, we demonstrated that the autocrine effect of IGF-I on MSC restored the fracture new bone formation and promoted the occurrence of a well-organized callus that bridged the gap. A callus that was basically absent in Irs1 -/- left untransplanted or transplanted with MSCs. We provided evidence of effects and mechanisms for transplanted MSC IGF in fracture repair and potentially to treat nonunions.

AB - Failures of fracture repair (nonunions) occur in 10% of all fractures. The use of mesenchymal stem cells (MSC) in tissue regeneration appears to be rationale, safe, and feasible. The contributions of MSC to the reparative process can occur through autocrine and paracrine effects. The primary objective of this study is to find a novel mean, by transplanting primary cultures of bone marrow-derived MSCs expressing insulin-like growth factor-I (MSC IGF), to promote these seed-and-soil actions of MSC to fully implement their regenerative abilities in fracture repair and nonunions. MSC IGF or traceable MSC IGF-Lac-Z were transplanted into wild-type or insulin-receptor-substrate knockout (Irs1 -/-) mice with a stabilized tibia fracture. Healing was assessed using biomechanical testing, microcomputed tomography (μCT), and histological analyses. We found that systemically transplanted MSC IGF through autocrine and paracrine actions improved the fracture mechanical strength and increased new bone content while accelerating mineralization. We determined that IGF-I adapted the response of transplanted MSC IGF to promote their differentiation into osteoblasts. In vitro and in vivo studies showed that IGF-I-induced osteoglastogenesis in MSCs was dependent of an intact IRS1-PI3K signaling. Furthermore, using Irs1 -/-mice as a nonunion fracture model through altered IGF signaling, we demonstrated that the autocrine effect of IGF-I on MSC restored the fracture new bone formation and promoted the occurrence of a well-organized callus that bridged the gap. A callus that was basically absent in Irs1 -/- left untransplanted or transplanted with MSCs. We provided evidence of effects and mechanisms for transplanted MSC IGF in fracture repair and potentially to treat nonunions.

KW - Fracture healing

KW - Insulin-like growth factor

KW - Mesenchymal stem cells

KW - Mouse models

UR - http://www.scopus.com/inward/record.url?scp=80053267201&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053267201&partnerID=8YFLogxK

U2 - 10.1002/stem.697

DO - 10.1002/stem.697

M3 - Article

VL - 29

SP - 1537

EP - 1548

JO - Stem Cells

JF - Stem Cells

SN - 1066-5099

IS - 10

ER -