Cambridge, MA, United States
Cambridge, MA, United States

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Jay S.M.,Harvard University | Jay S.M.,Harvard Stem Cell Institute | Jay S.M.,Brigham Regenerative Medicine Center | Lee R.T.,Harvard University | And 2 more authors.
Circulation Research | Year: 2013

A number of new and innovative approaches for repairing damaged myocardium are currently undergoing investigation, with several encouraging results. In addition to the progression of stem cell-based approaches and gene therapy/silencing methods, evidence continues to emerge that protein therapeutics may be used to directly promote cardiac repair and even regeneration. However, proteins are often limited in their therapeutic potential by short local half-lives and insufficient bioavailability and bioactivity, and many academic laboratories studying cardiovascular diseases are more comfortable with molecular and cellular biology than with protein biochemistry. Protein engineering has been used broadly to overcome weaknesses traditionally associated with protein therapeutics and has the potential to specifically enhance the efficacy of molecules for cardiac repair. However, protein engineering as a strategy has not yet been used in the development of cardiovascular therapeutics to the degree that it has been used in other fields. In this review, we discuss the role of engineered proteins in cardiovascular therapies to date. Further, we address the promise of applying emerging protein engineering technologies to cardiovascular medicine and the barriers that must be overcome to enable the ultimate success of this approach. © 2013 American Heart Association, Inc.

Senyo S.E.,Harvard University | Senyo S.E.,Brigham Regenerative Medicine Center | Senyo S.E.,Harvard Stem Cell Institute | Lee R.T.,Harvard University | And 5 more authors.
Stem Cell Research | Year: 2014

Cardiomyocyte proliferation and progenitor differentiation are endogenous mechanisms of myocardial development. Cardiomyocytes continue to proliferate in mammals for part of post-natal development. In adult mammals under homeostatic conditions, cardiomyocytes proliferate at an extremely low rate. Because the mechanisms of cardiomyocyte generation provide potential targets for stimulating myocardial regeneration, a deep understanding is required for developing such strategies. We will discuss approaches for examining cardiomyocyte regeneration, review the specific advantages, challenges, and controversies, and recommend approaches for interpretation of results. We will also draw parallels between developmental and regenerative principles of these mechanisms and how they could be targeted for treating heart failure. © 2014.

Florine E.M.,Massachusetts Institute of Technology | Miller R.E.,Rush University Medical Center | Liebesny P.H.,Massachusetts Institute of Technology | Mroszczyk K.A.,Massachusetts Institute of Technology | And 3 more authors.
Tissue Engineering - Part A | Year: 2015

Heparin-binding insulin-like growth factor 1 (HB-IGF-1) is a fusion protein of IGF-1 with the HB domain of heparin-binding epidermal growth factor-like growth factor. A single dose of HB-IGF-1 has been shown to bind specifically to cartilage and to promote sustained upregulation of proteoglycan synthesis in cartilage explants. Achieving strong integration between native cartilage and tissue-engineered cartilage remains challenging. We hypothesize that if a growth factor delivered by the tissue engineering scaffold could stimulate enhanced matrix synthesis by both the cells within the scaffold and the adjacent native cartilage, integration could be enhanced. In this work, we investigated methods for adsorbing HB-IGF-1 to self-assembling peptide hydrogels to deliver the growth factor to encapsulated chondrocytes and cartilage explants cultured with growth factor-loaded hydrogels. We tested multiple methods for adsorbing HB-IGF-1 in self-assembling peptide hydrogels, including adsorption prior to peptide assembly, following peptide assembly, and with/without heparan sulfate (HS, a potential linker between peptide molecules and HB-IGF-1). We found that HB-IGF-1 and HS were retained in the peptide for all tested conditions. A subset of these conditions was then studied for their ability to stimulate increased matrix production by gel-encapsulated chondrocytes and by chondrocytes within adjacent native cartilage. Adsorbing HB-IGF-1 or IGF-1 prior to peptide assembly was found to stimulate increased sulfated glycosaminoglycan per DNA and hydroxyproline content of chondrocyte-seeded hydrogels compared with basal controls at day 10. Cartilage explants cultured adjacent to functionalized hydrogels had increased proteoglycan synthesis at day 10 when HB-IGF-1 was adsorbed, but not IGF-1. We conclude that delivery of HB-IGF-1 to focal defects in cartilage using self-assembling peptide hydrogels is a promising technique that could aid cartilage repair via enhanced matrix production and integration with native tissue. © Mary Ann Liebert, Inc. 2015.

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