Cell Growth and Differentiation – Parenchymal Regeneration

00:01 What's required for that cell growth to fill in the gaps? You need both soluble mediators and extracellular matrix.

00:10 Okay, so we're gonna talk about those in turn.

00:12 First up, soluble mediators.

00:15 And most of these are labeled with the term "growth factor" of some sort.

00:21 We'll talk about these. We'll give them all kinds of names.

00:24 But they're only called growth factors in part, because the first time that someone isolated them in a laboratory, the assay that they used was cellular proliferation.

00:36 So they got to call them a growth factor.

00:37 But in many cases, they do much, much more than just cause cell proliferation.

00:43 So, what's in a name? A growth factor can also cause cell differentiation.

00:48 It can change the phenotype of the cell.

00:50 It can change its behavior.

00:52 So for example, growth factors acting on endothelial cells can increase their permeability, having nothing to do with growth.

01:01 They can change the synthetic activity.

01:03 So again, having nothing to do with proliferation, but everything to do with making more matrix.

01:07 So the extracellular matrix.

01:08 They can be just chemotactic agents.

01:11 So sometimes they get labeled as a growth factor, because the assay said they stimulate cell growth, but really, their main day job is to cause cells to chemotaxis in a particular direction.

01:22 So keep that in mind when we hear "growth factor" it's not just perforation.

01:28 Remember, I've talked about these "factors"? Again, not at any textbooks.

01:31 These are factors that just help you, give you a framework for thinking about the healing process.

01:38 So, factor 1 in the sequence was interferon gamma.

01:41 Factor 2, was interleukin 1 and TNF, a twofer, because they had very similar profiles.

01:47 Factor 3, is Epidermal Growth Factor or EGF.

01:51 There are actually hundreds, literally hundreds of growth factors that will have similar effects. I've just picked one.

02:00 But in any particular tissue, there may be other more important growth factors.

02:06 So in liver, we will talk about hepatocyte growth factor.

02:11 Epidermal is good for skin, but there may be other growth factors, and other tissues.

02:15 So just keep in mind that this is just a example.

02:19 But we're gonna call it factor 3.

02:22 Epidermal growth factor is truly mitogenic.

02:24 Meaning it drives the proliferation of fibroblasts in epithelium.

02:29 Epithelium is epidermis. Can be epidermis, or skin, but epithelium can also be GI tract.

02:35 It can be other things, and clearly this growth factor also stimulates fibroblasts.

02:39 So it's what's in a name, right? Okay, it is synthesized by activated macrophages? Well, of course, yes, that's part of the regenerative process.

02:49 So it's probably activated into macrophages that are the major source for epidermal growth factor and other similar growth factors.

02:58 Turns out that epithelial cells that respond to epidermal growth factor can also make it.

03:04 Yet another example of an autocrine feed-forward loop.

03:08 So don't get too bogged down with that one.

03:11 This epidermal growth factor (EGF) has homology to transforming growth factor-alpha.

03:15 So, I could very easily have said, "Factor 3 was transforming growth factor-alpha." Instead, I said it was EGF.

03:23 There are many growth factors that have similar profiles.

03:26 And here's an important kind of name.

03:30 So you'd think, "Oh, my God, transforming growth factor, that must be involved in malignancy.

03:34 Well, no, not really.

03:35 Although the original assay did show that it could transform cells into a malignant state.

03:42 Okay, so epidermal growth factor, what does it do? So, it drives the proliferation, as we talked about, of epithelial cells and fibroblasts.

03:52 So a general kind of paradigm concept related to growth factors within the extracellular matrix, some of them are secreted de novo as we need them.

04:04 So EGF, transforming growth factor-alpha, platelet derived growth factor, interleukin-1, tumor necrosis factor, vascular endothelial growth factor, that's what all that alphabet soup means.

04:17 Those are all made as we need them, they're secreted de novo.

04:22 That's one way that we can regulate them.

04:24 The others I think this is actually much more nuanced, is that you make them make the factors in an inactive form, secrete them into the matrix, and they're ready to go if injury occurs.

04:39 That's pretty cool.

04:40 So there are some such as basic fibroblast growth factor abbreviated bFGF, that is secreted in an inactive form bound up to extracellular matrix heparin.

04:53 And transforming growth factor-beta is also out there in the matrix preformed ready to rock and roll, but we need to proteolytically cleaved.

05:05 So both of these will get activated in various forms when there is injury.

05:08 And it's actually kind of a clever way to provide growth factors exactly where you need them immediately.

05:14 You don't have to synthesize them.

05:16 But we use both kind of strategies to make these growth factors.