A PDGFRalpha perspective on PDGF signalling in developmental and pathological processes

Platelet-derived growth factors PDGFs are a family of ligands and receptors that regulate multiple processes of paramount importance during embryonic development. They are also involved in several pathological events, spanning from tumours to fibrotic diseases. PDGFs have been studied for more than 30 years, but the mechanisms, as well as the tissue and cell type specific physiological roles of PDGF biology are still not fully understood.

The work presented in this thesis investigates the role of PDGFR-alpha in cell differentiation during cardiac tissue specification, and the effects of PDGF overexpression in the myocardium during development and in the context of cardiac injury. We also examine the elusive function of the PDGF-A retention motif in PDGFR-alpha signalling during morphogenesis. The adoption of a reporter construct knocked into the PDGFR-alpha locus allowed us to precisely follow its site of expression.

Here we report evidence of a role for PDGFR-alpha signalling in the recruitment and differentiation of second heart field-derived cells during cardiac inflow tract development (paper I).

We also studied of the physiological role of the PDGF-A retention motif and the effects of its ablation. This work points to a preponderant role for the diffusible isoform in PDGFR-alpha signalling (paper II).

The data presented in paper III investigate the effects of PDGF-A and PDGF-B overexpression in the developing mouse myocardium, and complements previously published reports on PDGF-C and PDGF-D overexpression in the same system. Our findings extend the evaluation of the role of PDGFs in myocardial fibrosis induction, and suggest PDGFR-alpha positive cells as the source of excessive extracellular matrix deposition in the heart in response to ectopic PDGF expression.

Ectopic expression of the different PDGF ligands in injured and inflamed cardiac tissue reveals an unexpected role for PDGFs in tissue recovery, that appears to be mediated by PDGFR-alpha signalling cells (paper IV).

Many questions remain open-ended regarding PDGF signalling. The work presented in this thesis points at new and interesting directions for future studies.

List of scientific papers

I. Cardiac malformations in PDGFR-alpha mutant embryos are associated with increased expression of WT1 and Nkx 2.5 in the second heart field. Noortje A. M. Bax, Steven B. Bleyl, Radiosa Gallini, Lambertus J. Wisse, Jennifer Hunter, Angelique A. M. Van Oorschot, Edris A. F. Mahtab, Heleen Lie-Venema, Marie-Jose Goumans, Christer Betsholtz, Adriana C. Gittenbergerde Groot (2010). Developmental dynamics 239: 2307-2317
https://doi.org/10.1002/dvdy.22363

II. Analysis of mice lacking the heparin-binding splice isoform of platelet-derived growth factor A. Johanna Andrae, Hans Ehrencrona, Radiosa Gallini, Mark Lal, Hao Ding, Christer Betsholtz (2013). Molecular and cellular biology 33: 4030-4040
https://doi.org/10.1128/MCB.00749-13

III. Isoform specific modulation of inflammation induced by adenoviral mediated delivery of PDGF in the adult heart. Radiosa Gallini, Jenni Huusko, Seppo Ylä-Herttuala, Christer Betsholtz, Johanna Andrae (2014). [Manuscript]

IV. PDGFR-alpha positive cells in PDGF-A and PDGF-B induced cardiac fibrosis in mouse. Radiosa Gallini, Per Lindblom, Cecilia Bondjers, Christer Betsholtz, Johanna Andrae (2014). [Manuscript]