A new three dimensional biomimetic hydrogel to deliver factors secreted by human mesenchymal stem cells in spinal cord injury.
Stem cell therapy with human mesenchymal stem cells (hMSCs) represents a promising strategy in spinal cord injury (SCI). However, both systemic and parenchymal hMSCs administrations show significant drawbacks as a limited number and viability of stem cells in situ. Biomaterials able to encapsulate and sustain hMSCs represent a viable approach to overcome these limitations potentially improving the stem cell therapy. In this study, we evaluate a new agarose/carbomer based hydrogel which combines different strategies to optimize hMSCs viability, density and delivery of paracrine factors. Specifically, we evaluate a new loading procedure on a lyophilized scaffold (soaked up effect) that reduces mechanical stress in encapsulating hMSCs into the hydrogel. In addition, we combine arginine-glycine-aspartic acid (RGD) tripeptide and 3D extracellular matrix deposition to increase the capacity to attach and maintain healthy hMSCs within the hydrogel over time. Furthermore, the fluidic diffusion from the hydrogel toward the injury site is improved by using a cling film that oriented efficaciously the delivery of paracrine factors in vivo. Finally, we demonstrate that an improved combination as here proposed of hMSCs and biomimetic hydrogel is able to immunomodulate significantly the pro-inflammatory environment in a SCI mouse model, increasing M2 macrophagic population and promoting a pro-regenerative environment in situ.
Dipartimento di Neuroscienze, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milan, Italy.
Ilaria
I
Caron
Dipartimento di Chimica, Materiali e Ingegneria Chimica "Giulio Natta", Politecnico di Milano, via Mancinelli 7, 20131 Milan, Italy.
Filippo
F
Rossi
Dipartimento di Neuroscienze, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milan, Italy.
Simonetta
S
Papa
Dipartimento di Neuroscienze, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milan, Italy.
Rossella
R
Aloe
Dipartimento di Neuroscienze, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milan, Italy.
Marika
M
Sculco
Dipartimento di Chimica, Materiali e Ingegneria Chimica "Giulio Natta", Politecnico di Milano, via Mancinelli 7, 20131 Milan, Italy.
Emanuele
E
Mauri
Dipartimento di Chimica, Materiali e Ingegneria Chimica "Giulio Natta", Politecnico di Milano, via Mancinelli 7, 20131 Milan, Italy.
Alessandro
A
Sacchetti
Dipartimento di Oncologia, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milan, Italy.
Eugenio
E
Erba
Dipartimento di Oncologia, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milan, Italy.
Nicolò
N
Panini
Unit of Cell Therapy and Cryobiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20122 Milan, Italy.
Valentina
V
Parazzi
Unit of Cell Therapy and Cryobiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20122 Milan, Italy.
Mario
M
Barilani
Dipartimento di Neuroscienze, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milan, Italy.
Gianluigi
G
Forloni
Department of Innovative Technologies, University of Applied Sciences and Arts of Southern Switzerland, SUPSI, via Cantonale, CH-6928 Manno, Switzerland.
Giuseppe
G
Perale
Unit of Cell Therapy and Cryobiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20122 Milan, Italy.
Lorenza
L
Lazzari
Dipartimento di Neuroscienze, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milan, Italy. Electronic address: pietro.veglianese@marionegri.it.
Pietro
P
Veglianese
D000818:Animals; D040761:Biomimetic Materials / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry / Q000494:pharmacology*; D007249:Inflammation / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000648:ultrastructure; D008810:Mice, Inbred C57BL; D044085:Microfluidics; D009842:Oligopeptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000628:therapy*
D009842:Oligopeptides; D012333:RNA, Messenger; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; C047981:arginyl-glycyl-aspartic acid
Extracellular matrix; Human mesenchymal stem cells; Hydrogels; Inflammation; Macrophages; Spinal cord injury