WEBVTT 00:00:16.412 --> 00:00:17.370 ADAM MARTIN: All right. 00:00:17.370 --> 00:00:20.580 So in Monday's lecture, we talked 00:00:20.580 --> 00:00:27.540 about how cells replicate, OK? 00:00:27.540 --> 00:00:32.880 And today, I want to talk about how now an entire organ would 00:00:32.880 --> 00:00:34.380 essentially replicate. 00:00:34.380 --> 00:00:36.540 In this case, it's not going to divide, 00:00:36.540 --> 00:00:42.240 but it's going to regenerate or renew itself, OK? 00:00:42.240 --> 00:00:50.400 And so this involves adult stem cells and also apoptosis , 00:00:50.400 --> 00:00:53.580 which you've heard a little bit about earlier in the course. 00:00:53.580 --> 00:00:57.450 And to explain this to you, I'm going to have basically a model 00:00:57.450 --> 00:00:59.250 organ that we'll use. 00:00:59.250 --> 00:01:02.490 And we'll use it for a couple lectures. 00:01:02.490 --> 00:01:07.020 And the model organ is going to be the lining of the intestine, 00:01:07.020 --> 00:01:08.070 OK? 00:01:08.070 --> 00:01:16.470 So the lining of the intestine is an epithelial tissue. 00:01:16.470 --> 00:01:19.160 And I'll tell you a little bit about epithelia 00:01:19.160 --> 00:01:20.490 in just a minute. 00:01:20.490 --> 00:01:24.220 But you have the intestinal epithelium. 00:01:24.220 --> 00:01:27.120 And this is the-- these are the cells that 00:01:27.120 --> 00:01:30.170 are the lining of the intestine, OK? 00:01:30.170 --> 00:01:34.170 And one of the reasons that I've chosen this system 00:01:34.170 --> 00:01:37.710 is because the lining of your intestine 00:01:37.710 --> 00:01:42.150 has pretty remarkable regenerative capabilities, OK? 00:01:42.150 --> 00:01:56.230 So your small intestine renews about every four to five days, 00:01:56.230 --> 00:01:56.730 OK? 00:01:56.730 --> 00:02:01.560 So the vast majority of your cells in the intestine 00:02:01.560 --> 00:02:05.820 were basically derived in the last four to five days, OK? 00:02:05.820 --> 00:02:11.550 So humans aren't as cool as some organisms, 00:02:11.550 --> 00:02:14.460 like newts, in that you can't cut off your arm 00:02:14.460 --> 00:02:15.810 and have it grow back. 00:02:15.810 --> 00:02:17.590 But at least we have the intestine, 00:02:17.590 --> 00:02:22.380 which undergoes a pretty dramatic regeneration, OK? 00:02:22.380 --> 00:02:24.330 And this is not-- 00:02:24.330 --> 00:02:26.790 the intestine is unique in how rapid this is. 00:02:26.790 --> 00:02:30.990 But you have other tissues that also exhibit continual renewal, 00:02:30.990 --> 00:02:33.990 like your skin and your blood cells. 00:02:33.990 --> 00:02:35.760 And even the cells of your that line 00:02:35.760 --> 00:02:39.150 your insides of your lungs, they do exhibit renewal 00:02:39.150 --> 00:02:41.090 capabilities, OK? 00:02:41.090 --> 00:02:45.090 And so I'm going to use the intestine as a model system. 00:02:45.090 --> 00:02:47.850 It doesn't mean it doesn't happen in other tissues. 00:02:47.850 --> 00:02:50.040 But it just happens that we can-- 00:02:50.040 --> 00:02:53.220 we really understand the intestine system 00:02:53.220 --> 00:02:55.620 maybe a little bit more than many other systems. 00:02:55.620 --> 00:02:59.170 So I'm going to use it as an example. 00:02:59.170 --> 00:03:02.490 So in thinking about the lining of your intestine, 00:03:02.490 --> 00:03:06.160 it's important, and it has important functions. 00:03:06.160 --> 00:03:08.130 One important function of this lining 00:03:08.130 --> 00:03:12.630 is it has to absorb nutrients from food going 00:03:12.630 --> 00:03:16.890 through your intestine, OK? 00:03:16.890 --> 00:03:26.560 So it exhibits a nutrient absorption function. 00:03:26.560 --> 00:03:30.660 Now, the lining of your intimate intestine, much like your skin, 00:03:30.660 --> 00:03:34.740 is also a barrier between the inside of your body 00:03:34.740 --> 00:03:36.410 and the outside world, right? 00:03:36.410 --> 00:03:40.080 Because basically, the inside of your intestine 00:03:40.080 --> 00:03:42.810 is contiguous with the outside world, right? 00:03:42.810 --> 00:03:45.120 If you open your mouth, you can get down 00:03:45.120 --> 00:03:48.000 to the inside of your intestine, OK? 00:03:48.000 --> 00:03:51.145 So it serves also an important barrier function. 00:03:57.190 --> 00:04:01.810 And one point I want to make about this system right now 00:04:01.810 --> 00:04:05.590 is that the intestinal epithelium, like many 00:04:05.590 --> 00:04:10.690 of your other organs, are composed of multiple cell 00:04:10.690 --> 00:04:12.490 types, OK? 00:04:12.490 --> 00:04:17.020 So it also has multiple cell types. 00:04:26.190 --> 00:04:26.690 OK. 00:04:26.690 --> 00:04:30.230 So let's now consider the lining of the intestine. 00:04:30.230 --> 00:04:36.140 And the way the intestine morphologically looks 00:04:36.140 --> 00:04:40.850 is that there are a series of invaginations. 00:04:40.850 --> 00:04:44.270 So this is a cross-section view through the intestine. 00:04:44.270 --> 00:04:47.300 So you have to imagine that this is a cross-section view, 00:04:47.300 --> 00:04:49.460 but that this is a plane. 00:04:49.460 --> 00:04:54.260 And it's a plane with a lot of invaginations in the plane, 00:04:54.260 --> 00:04:56.970 but also protrusions out of the plane. 00:04:56.970 --> 00:04:58.365 And so you have to remember-- 00:04:58.365 --> 00:04:59.990 you have to think of this as a surface. 00:04:59.990 --> 00:05:02.600 And then it's wrapped up into a tube, OK? 00:05:02.600 --> 00:05:05.780 So this is just a very simple cross-section image 00:05:05.780 --> 00:05:09.800 of the intestine, OK? 00:05:09.800 --> 00:05:13.430 And the lining of the intestine is a sheet of cells. 00:05:16.500 --> 00:05:21.330 So this lining is composed of many, many cells. 00:05:21.330 --> 00:05:23.270 They're columnar in morphology. 00:05:29.970 --> 00:05:32.420 So what I've drawn here is just a small section 00:05:32.420 --> 00:05:33.900 of the intestine. 00:05:33.900 --> 00:05:37.160 This would be the lumen, out here. 00:05:37.160 --> 00:05:41.420 This is where the food is, or the food 00:05:41.420 --> 00:05:44.390 going through your intestine would be. 00:05:44.390 --> 00:05:51.860 And then below here, this is interstitial fluid inside 00:05:51.860 --> 00:05:57.530 of your body basically, interstitial, OK? 00:05:57.530 --> 00:05:58.700 So the food's up here. 00:05:58.700 --> 00:06:01.880 The rest of your body is down here. 00:06:01.880 --> 00:06:04.940 And you can see that there are there 00:06:04.940 --> 00:06:06.110 there's a structure to it. 00:06:06.110 --> 00:06:08.750 It's not just a flat surface that's wrapped up, 00:06:08.750 --> 00:06:10.970 but there are invaginations. 00:06:10.970 --> 00:06:18.640 And the invaginations are known as intestinal crypts, right? 00:06:18.640 --> 00:06:22.180 Much like you would-- 00:06:22.180 --> 00:06:26.770 if you bury something, like a body, it would go below ground. 00:06:26.770 --> 00:06:31.990 So the crypt is below the surface of the lumen. 00:06:31.990 --> 00:06:37.780 And this these projections, out here, are known as villi. 00:06:37.780 --> 00:06:40.420 So they're the villi of your gut, OK? 00:06:43.890 --> 00:06:47.000 Now, if we consider-- 00:06:47.000 --> 00:06:49.770 and this lining is made up of multiple cell 00:06:49.770 --> 00:06:51.750 types, which I've outlined up here 00:06:51.750 --> 00:06:53.100 and which are in your handout. 00:06:53.100 --> 00:06:54.870 So you don't have to write these down. 00:06:54.870 --> 00:06:56.340 But this is just making the point 00:06:56.340 --> 00:06:59.380 that there are various differentiated cell types. 00:06:59.380 --> 00:07:02.190 There are enterocytes, which are the absorptive cells. 00:07:02.190 --> 00:07:04.410 These are the cells that are taking in nutrients 00:07:04.410 --> 00:07:07.070 and transporting them into your body. 00:07:07.070 --> 00:07:09.780 There are enteroendocrine cells that 00:07:09.780 --> 00:07:12.780 play an important signaling function in the gut to regulate 00:07:12.780 --> 00:07:15.110 the biology of the gut system. 00:07:15.110 --> 00:07:17.970 There are a goblet cells, which secrete mucus 00:07:17.970 --> 00:07:22.230 into the intestine system, which protects these epithelial cells 00:07:22.230 --> 00:07:26.400 from digestive enzymes that are present in the lumen. 00:07:26.400 --> 00:07:29.910 And there is this last cell type, the paneth cell, 00:07:29.910 --> 00:07:33.750 which functions as an important role in regulating stem cells, 00:07:33.750 --> 00:07:36.310 as I'll outline in just a minute. 00:07:36.310 --> 00:07:39.570 So these are all the differentiated cell types. 00:07:39.570 --> 00:07:41.760 But there's a type of cell that's 00:07:41.760 --> 00:07:44.040 an undifferentiated cell type. 00:07:44.040 --> 00:07:46.720 And that's the intestinal stem cell, 00:07:46.720 --> 00:07:50.260 which will be the hero of today's lecture. 00:07:50.260 --> 00:07:50.760 All right. 00:07:50.760 --> 00:07:55.740 Now, if we consider just a small group of cells, 00:07:55.740 --> 00:07:59.040 what these cells look like is this, OK? 00:07:59.040 --> 00:08:03.350 So these are what are known as epithelial cells. 00:08:03.350 --> 00:08:07.780 And epithelial cells have certain properties. 00:08:07.780 --> 00:08:11.250 The first is you see that this end of the epithelial cell 00:08:11.250 --> 00:08:14.070 looks different from this end, OK? 00:08:14.070 --> 00:08:18.810 And this is called an apical-basal polarity. 00:08:23.670 --> 00:08:26.050 So much like neurons have a polarity where 00:08:26.050 --> 00:08:28.830 the on one side of the neuron there are dendrites 00:08:28.830 --> 00:08:31.720 and on the other side of the neuron there's an axon, 00:08:31.720 --> 00:08:34.530 these cells have another type of polarity, which is 00:08:34.530 --> 00:08:37.090 called apical-basal polarity. 00:08:37.090 --> 00:08:40.500 So the side facing the lumen is apical. 00:08:40.500 --> 00:08:42.840 So the lumen would be up here. 00:08:42.840 --> 00:08:46.590 And the basal side would be down here, OK? 00:08:46.590 --> 00:08:52.790 So this is basically oriented along this axis of the tissue, 00:08:52.790 --> 00:08:53.510 OK? 00:08:53.510 --> 00:08:58.920 where apical is on this side, basal is on this side, OK? 00:08:58.920 --> 00:09:03.990 And these projections from the individual cell, these 00:09:03.990 --> 00:09:08.040 are called microvilli. 00:09:08.040 --> 00:09:10.620 And essentially, these plasma membrane 00:09:10.620 --> 00:09:13.860 corrugations increase the surface area 00:09:13.860 --> 00:09:18.840 through which nutrients can be absorbed into these cells, OK? 00:09:18.840 --> 00:09:23.370 Now, one other defining feature of these cells 00:09:23.370 --> 00:09:26.170 is they have proteins that protrude from the plasma 00:09:26.170 --> 00:09:26.670 membrane. 00:09:31.420 --> 00:09:35.950 And these are adhesion proteins that couple the cells together. 00:09:35.950 --> 00:09:37.780 And actually, the cells are stuck together 00:09:37.780 --> 00:09:40.210 much tighter than I'm drawing here, such 00:09:40.210 --> 00:09:42.640 that the cells form a barrier so that things 00:09:42.640 --> 00:09:47.530 can pass unregulated from the lumen into the body, OK? 00:09:47.530 --> 00:09:50.260 But these proteins, which I'm drawing 00:09:50.260 --> 00:09:52.930 sticking out of the membranes of the cells, 00:09:52.930 --> 00:09:53.950 are adhesion proteins. 00:10:00.560 --> 00:10:03.220 And these adhesion proteins simply 00:10:03.220 --> 00:10:06.160 link the cells together such that they form 00:10:06.160 --> 00:10:09.370 a sheet of cells or tissue. 00:10:09.370 --> 00:10:16.490 So they link cells together, OK? 00:10:16.490 --> 00:10:20.830 So these are two of the key properties of epithelia. 00:10:20.830 --> 00:10:23.200 They have an apical-basal polarity. 00:10:23.200 --> 00:10:26.230 And they also exhibit cell-to-cell adhesion, 00:10:26.230 --> 00:10:29.560 such as the cells reach out and connect to each other. 00:10:29.560 --> 00:10:32.890 And they basically are glued together, or Velcroed together 00:10:32.890 --> 00:10:34.990 such that they don't easily come apart. 00:10:39.170 --> 00:10:39.670 OK. 00:10:39.670 --> 00:10:42.760 Now, in considering this system, what I'm going to tell 00:10:42.760 --> 00:10:47.890 you is that there is renewal of this lining. 00:10:47.890 --> 00:10:53.723 And the renewal starts at the base of the crypts, OK? 00:10:53.723 --> 00:10:55.015 So there's going to be renewal. 00:10:57.610 --> 00:11:05.320 And this cell renewal is at the base of the crypts, right? 00:11:05.320 --> 00:11:07.020 There are many of these crypts, right? 00:11:07.020 --> 00:11:08.840 You have you have like the surface, 00:11:08.840 --> 00:11:11.260 but there are many, many invaginations 00:11:11.260 --> 00:11:15.000 that are present in your gut. 00:11:15.000 --> 00:11:20.890 And the renewal is happening at the base of these crypts, OK? 00:11:20.890 --> 00:11:23.950 And that's because at the base of these crypts 00:11:23.950 --> 00:11:30.460 are where a type of cell, known as intestinal stem cells, lie, 00:11:30.460 --> 00:11:31.600 OK? 00:11:31.600 --> 00:11:33.970 So it's at the base of these crypts 00:11:33.970 --> 00:11:38.470 where there are what are known as intestinal stem cells. 00:11:41.740 --> 00:11:45.070 And I'm going to abbreviate these ISCs for this, 00:11:45.070 --> 00:11:47.980 so I don't have to write out intestinal stem cell 00:11:47.980 --> 00:11:51.490 whenever I tell you about them, OK? 00:11:51.490 --> 00:11:53.530 Now, that's where renewal occurs. 00:11:53.530 --> 00:11:57.070 And if you just had more and more cells getting 00:11:57.070 --> 00:12:00.970 put in the system without any removal of cells, 00:12:00.970 --> 00:12:03.700 then the organ would get bigger and bigger, right? 00:12:03.700 --> 00:12:06.490 And so our intestine more or less 00:12:06.490 --> 00:12:10.490 staying the same size at this point in our life. 00:12:10.490 --> 00:12:18.130 And so in addition to renewal, there's also cell death. 00:12:18.130 --> 00:12:21.130 And what happens when cell death occurs 00:12:21.130 --> 00:12:24.430 is that cells are shed from the intestinal lining 00:12:24.430 --> 00:12:26.000 into the lumen. 00:12:26.000 --> 00:12:31.765 So cells are shed into the lumen. 00:12:35.870 --> 00:12:39.280 And then they just go with the rest of the crap that's 00:12:39.280 --> 00:12:40.660 in your intestinal lumen. 00:12:40.660 --> 00:12:45.100 And it's eventually removed from the body, OK? 00:12:45.100 --> 00:12:49.930 So some cells are leaving the tissue and going into the lumen 00:12:49.930 --> 00:12:54.670 after they've existed for a few days in the intestine, OK? 00:12:54.670 --> 00:12:58.960 So to have an organ then the constant size 00:12:58.960 --> 00:13:03.350 renewal has to essentially be more or less equal to death, 00:13:03.350 --> 00:13:03.850 OK? 00:13:03.850 --> 00:13:07.510 And so you can think of this as a type of homeostatic state 00:13:07.510 --> 00:13:12.550 for this tissue where, if renewal equals death, you have 00:13:12.550 --> 00:13:18.580 what is known as tissue homeostasis, where 00:13:18.580 --> 00:13:21.730 the number of cells in the system as a whole 00:13:21.730 --> 00:13:25.180 is basically remaining the same, even though there's constantly 00:13:25.180 --> 00:13:27.740 new cells going into this system. 00:13:27.740 --> 00:13:29.140 But then the cells are also-- 00:13:29.140 --> 00:13:31.530 the older cells are being removed from the system. 00:13:38.380 --> 00:13:41.230 So what's really key in this process 00:13:41.230 --> 00:13:43.420 are these intestinal stem cells. 00:13:43.420 --> 00:13:47.200 So I'm first going to tell you about stem cells. 00:13:47.200 --> 00:13:55.680 And these are what I would define as adult stem cells, OK? 00:13:55.680 --> 00:13:58.330 So they're stem cells that are associated 00:13:58.330 --> 00:14:01.000 with a particular organ, OK? 00:14:01.000 --> 00:14:02.770 And I want to differentiate this right 00:14:02.770 --> 00:14:06.730 now between these types of stem cells 00:14:06.730 --> 00:14:08.950 and another type of stem cell that we're 00:14:08.950 --> 00:14:11.530 going to talk about later in the course, which 00:14:11.530 --> 00:14:13.120 is an embryonic stem cell. 00:14:19.620 --> 00:14:22.150 So adult stem cells-- 00:14:22.150 --> 00:14:27.420 these stem cells, like intestinal stem cells, 00:14:27.420 --> 00:14:34.665 are associated with a specific organ. 00:14:39.210 --> 00:14:42.420 And they only give rise to cell types that 00:14:42.420 --> 00:14:45.300 are present in that organ, OK? 00:14:45.300 --> 00:14:50.050 So they're not-- they can't give rise to any type of cell type. 00:14:50.050 --> 00:14:53.880 Your adult stem cells are really specific-- organ-specific, 00:14:53.880 --> 00:14:55.200 we'll say. 00:14:55.200 --> 00:15:00.000 In contrast, embryonic stem cells are-- 00:15:00.000 --> 00:15:03.520 these stem cells have more possibilities. 00:15:03.520 --> 00:15:06.270 They can give rise to pretty much any cell 00:15:06.270 --> 00:15:09.180 type in an entire organism, OK? 00:15:09.180 --> 00:15:11.280 So you can think of these adult stem cells 00:15:11.280 --> 00:15:14.790 as being more restricted in their fates 00:15:14.790 --> 00:15:17.260 than the embryonic stem cells. 00:15:17.260 --> 00:15:21.660 And so what adult stem cells are called 00:15:21.660 --> 00:15:26.190 is they're called multipotent, because they can give rise 00:15:26.190 --> 00:15:28.630 to multiple different cell types, 00:15:28.630 --> 00:15:30.690 but not all of the cell types that are 00:15:30.690 --> 00:15:33.000 present in an organism, right? 00:15:33.000 --> 00:15:36.570 An intestinal stem cell will not be giving rise 00:15:36.570 --> 00:15:42.490 to a blood cell or other cell types in other organs, right? 00:15:42.490 --> 00:15:44.880 It's restricted to just giving rise 00:15:44.880 --> 00:15:47.910 to cells that are present in that organ. 00:15:47.910 --> 00:15:50.460 In contrast, embryonic stem cells 00:15:50.460 --> 00:15:56.280 are what are known as totipotent, or sometimes 00:15:56.280 --> 00:16:00.810 pluripotent, where this type of cell 00:16:00.810 --> 00:16:04.440 really is capable of making any type of cell that 00:16:04.440 --> 00:16:08.370 is present in an adult organism, OK? 00:16:08.370 --> 00:16:11.400 So that's less restricted than the adult stem cells. 00:16:11.400 --> 00:16:14.100 And we're going to come back to these embryonic stem cells 00:16:14.100 --> 00:16:16.270 towards the end of the course. 00:16:16.270 --> 00:16:19.710 But for understanding cancer and also 00:16:19.710 --> 00:16:22.320 tissue homeostasis in the intestine, 00:16:22.320 --> 00:16:24.930 we're really needing to focus on the adult stem cells. 00:16:28.300 --> 00:16:28.800 OK. 00:16:28.800 --> 00:16:32.620 So these adult stem cells have two key properties. 00:16:32.620 --> 00:16:34.710 The first is what I just said. 00:16:34.710 --> 00:16:35.850 They're multipotent. 00:16:41.500 --> 00:16:43.830 And what multipotent means is that they 00:16:43.830 --> 00:16:48.510 can give rise to multiple different cell types. 00:16:48.510 --> 00:16:54.645 So this stem cell gives rise to multiple cell types. 00:17:00.270 --> 00:17:03.420 And this is associated usually with a single organ system. 00:17:10.619 --> 00:17:11.119 OK. 00:17:11.119 --> 00:17:14.760 So in the case of the intestinal stem cell, 00:17:14.760 --> 00:17:18.119 the intestinal stem cell is multipotent. 00:17:18.119 --> 00:17:20.490 And it can give rise to many different terminally 00:17:20.490 --> 00:17:22.480 differentiated cells. 00:17:22.480 --> 00:17:25.890 And you can see here I've just written in example cell types 00:17:25.890 --> 00:17:28.349 that the intestinal cell could generate. 00:17:28.349 --> 00:17:31.140 It can generate any of the four different types of cells 00:17:31.140 --> 00:17:35.850 that I introduced to you at the beginning of the lecture. 00:17:35.850 --> 00:17:38.850 The other key aspect of this system 00:17:38.850 --> 00:17:41.010 is that, in addition to generating 00:17:41.010 --> 00:17:43.740 all of these different cell types, 00:17:43.740 --> 00:17:47.610 the stem cell can also renew itself, OK? 00:17:47.610 --> 00:17:51.810 So the other key property is this self-renewal. 00:17:56.230 --> 00:18:05.280 So the intestinal stem cell also gives rise 00:18:05.280 --> 00:18:10.200 to another intestinal stem cell. 00:18:10.200 --> 00:18:13.260 So it basically duplicates itself such 00:18:13.260 --> 00:18:16.620 that you still have a stem cell in the organ. 00:18:16.620 --> 00:18:19.830 And then one of the daughter cells 00:18:19.830 --> 00:18:23.080 is self-renewed and remains a stem cell. 00:18:23.080 --> 00:18:26.640 The other daughter cell can go on to divide 00:18:26.640 --> 00:18:30.780 further and give rise to these differentiated cell types, OK? 00:18:39.000 --> 00:18:39.500 All right. 00:18:39.500 --> 00:18:41.660 So one question you might be asking 00:18:41.660 --> 00:18:45.860 yourself is, how is it that-- 00:18:45.860 --> 00:18:49.160 what regulates whether or not a cell 00:18:49.160 --> 00:18:52.370 will go on to differentiate or whether it 00:18:52.370 --> 00:18:56.780 will stay a stem cell? 00:18:56.780 --> 00:18:59.300 And the answer to this question involves 00:18:59.300 --> 00:19:01.520 communication between this stem cell 00:19:01.520 --> 00:19:05.480 and other cells in the system. 00:19:05.480 --> 00:19:09.110 And it involves a special type of cell 00:19:09.110 --> 00:19:11.810 called a stem cell niche cell. 00:19:11.810 --> 00:19:14.900 And so I'm going to tell you about a model, which 00:19:14.900 --> 00:19:17.210 is the stem cell niche model. 00:19:17.210 --> 00:19:19.445 And what the stem cell niche model is, 00:19:19.445 --> 00:19:23.870 is that basically there is a niche or compartment which 00:19:23.870 --> 00:19:28.490 promotes the self-renewal of cells in that compartment that 00:19:28.490 --> 00:19:30.300 makes them stem cells. 00:19:30.300 --> 00:19:36.890 So the stem cell niche you can think of as a compartment where 00:19:36.890 --> 00:19:43.070 signals, similar to the types of signals that we've been talking 00:19:43.070 --> 00:19:46.220 about over the past four or five lectures, 00:19:46.220 --> 00:19:49.940 regulate the behavior of the cell to ensure self-renewal 00:19:49.940 --> 00:19:53.420 and to suppress differentiation, so a compartment 00:19:53.420 --> 00:19:58.625 where signals promote stem cell renewal. 00:20:09.550 --> 00:20:13.360 I want to ask you one question before I move on, which 00:20:13.360 --> 00:20:15.970 is, how would you define-- 00:20:15.970 --> 00:20:17.980 how would you determine that there 00:20:17.980 --> 00:20:20.860 is a special type of cell that gives rise to all 00:20:20.860 --> 00:20:24.280 of the cells in an organ? 00:20:24.280 --> 00:20:29.740 If you were tasked with finding this and determining 00:20:29.740 --> 00:20:32.650 whether this was true or not, how might you do it? 00:20:32.650 --> 00:20:35.980 Does anyone have an idea of what experiment they would do, 00:20:35.980 --> 00:20:40.300 or what criteria they would have to determine whether or not 00:20:40.300 --> 00:20:41.140 this is a case? 00:20:49.990 --> 00:20:53.140 Let's say I gave you a cell, right? 00:20:53.140 --> 00:20:54.910 In a dish. 00:20:54.910 --> 00:20:57.850 And I asked you to tell me whether or not 00:20:57.850 --> 00:21:01.450 you would think this is a stem cell or not. 00:21:01.450 --> 00:21:03.795 Yes, miles? 00:21:03.795 --> 00:21:09.500 AUDIENCE: [INAUDIBLE] 00:21:09.500 --> 00:21:10.586 ADAM MARTIN: Mm-hmm. 00:21:10.586 --> 00:21:13.051 AUDIENCE: One cell is produced by the same cell, 00:21:13.051 --> 00:21:16.995 assuming that it's not a stem cell 00:21:16.995 --> 00:21:25.637 but if the cell [INAUDIBLE] it's a stem cell. 00:21:25.637 --> 00:21:26.470 ADAM MARTIN: Mm-hmm. 00:21:26.470 --> 00:21:30.580 So Miles suggested he would like to take the cell that I just 00:21:30.580 --> 00:21:34.780 gifted him, and let it grow up, and determine whether it gives 00:21:34.780 --> 00:21:37.000 rise to multiple cell types. 00:21:37.000 --> 00:21:39.370 And Miles said that, if it just gave rise 00:21:39.370 --> 00:21:41.500 to a single cell type, that would suggest 00:21:41.500 --> 00:21:43.310 that it's not a stem cell. 00:21:43.310 --> 00:21:46.690 But if it gave rise to multiple cell types, 00:21:46.690 --> 00:21:49.450 then it could be a stem cell, OK? 00:21:49.450 --> 00:21:53.110 And it's this type of experiment that-- 00:21:53.110 --> 00:21:55.480 this type of experiment has been done, 00:21:55.480 --> 00:22:00.160 where you can take an intestine from mice, 00:22:00.160 --> 00:22:02.770 and even you can take tissue from humans, 00:22:02.770 --> 00:22:05.480 and you can associate the cells from each other 00:22:05.480 --> 00:22:09.520 so that you're left with single cells that are separate. 00:22:09.520 --> 00:22:13.030 And you can then use some type of flow cytometry 00:22:13.030 --> 00:22:14.710 to separate cells. 00:22:14.710 --> 00:22:16.900 And you might be interested in a cell that 00:22:16.900 --> 00:22:20.260 maybe expresses some marker that you're interested in. 00:22:20.260 --> 00:22:23.710 And you can separate those cells and isolate them. 00:22:23.710 --> 00:22:26.530 And then you can take an individual cell 00:22:26.530 --> 00:22:29.200 and grow it in a dish, OK? 00:22:29.200 --> 00:22:32.840 And this has been done for intestinal stem cells. 00:22:32.840 --> 00:22:35.590 And if you take an intestinal stem cell 00:22:35.590 --> 00:22:38.140 and you grow it in a dish, it can grow up 00:22:38.140 --> 00:22:40.780 and form a bulk of tissue. 00:22:40.780 --> 00:22:44.650 But what's really remarkable about the result 00:22:44.650 --> 00:22:48.100 of this experiment is that, from a stem cell, 00:22:48.100 --> 00:22:50.290 you get this massive tissue. 00:22:50.290 --> 00:22:53.380 But it self--organizes into a structure that very much 00:22:53.380 --> 00:22:59.150 resembles a normal gut, meaning that there are crypts where 00:22:59.150 --> 00:23:01.740 the stem cells are localized. 00:23:01.740 --> 00:23:03.490 And then if you look at the different cell 00:23:03.490 --> 00:23:06.580 types in this, what's known as an organoid, 00:23:06.580 --> 00:23:10.570 you see all of the different cell types that are normally 00:23:10.570 --> 00:23:12.850 present in the gut, OK? 00:23:12.850 --> 00:23:16.090 And so this is an example of a type of experiment 00:23:16.090 --> 00:23:19.150 that's done to show whether or not 00:23:19.150 --> 00:23:22.780 a certain cell has the capability of functioning 00:23:22.780 --> 00:23:24.190 like a stem cell, OK? 00:23:24.190 --> 00:23:26.080 So if you start with a stem cell, 00:23:26.080 --> 00:23:30.820 you can regenerate the entire organ system essentially. 00:23:30.820 --> 00:23:34.360 You might also be familiar with bone marrow transplants. 00:23:34.360 --> 00:23:39.760 And so if you kill all the hematopoietic stem cells 00:23:39.760 --> 00:23:42.460 in, let's say, a mouse, then you can 00:23:42.460 --> 00:23:45.700 transplant in a single hematopoietic stem cell 00:23:45.700 --> 00:23:46.870 into that system. 00:23:46.870 --> 00:23:52.990 And it will regenerate all the blood cells in that system, OK? 00:23:52.990 --> 00:23:57.010 So those are just a few examples of how one might functionally 00:23:57.010 --> 00:23:59.860 define a stem cell in an experimental setting. 00:24:02.480 --> 00:24:02.980 All right. 00:24:02.980 --> 00:24:06.190 So now, I want to tell you about the types of signals 00:24:06.190 --> 00:24:09.960 and how these signals are promoting stem cell renewal, 00:24:09.960 --> 00:24:10.630 OK? 00:24:10.630 --> 00:24:13.720 So in this case, the niche, stem cell niche 00:24:13.720 --> 00:24:14.920 is going to be right here. 00:24:17.910 --> 00:24:20.020 And the types of signals involved-- 00:24:20.020 --> 00:24:23.440 I'll just draw some cells here. 00:24:23.440 --> 00:24:26.230 One of the types of cells that's part 00:24:26.230 --> 00:24:29.440 of the niche in the intestine is the cell type 00:24:29.440 --> 00:24:31.705 that I introduced you as the paneth cell. 00:24:34.360 --> 00:24:38.230 And these paneth cells localized to the base of the crypts 00:24:38.230 --> 00:24:41.230 together with the intestinal stem cells. 00:24:41.230 --> 00:24:44.950 And what paneth cells do is they send a signal 00:24:44.950 --> 00:24:46.960 to neighboring cells. 00:24:46.960 --> 00:24:49.420 And this signal is a Wnt signal, which I'll tell you 00:24:49.420 --> 00:24:51.050 about in just a minute. 00:24:51.050 --> 00:24:54.100 And so this is the intestinal stem cell here. 00:24:54.100 --> 00:24:58.660 And the paneth cell is signaling to that intestinal stem cell 00:24:58.660 --> 00:25:02.950 through a secreted ligand known as Wnt. 00:25:02.950 --> 00:25:04.870 So Wnt is a secreted ligand. 00:25:08.600 --> 00:25:17.300 And this signal is what's known as a juxtacrine signal, which 00:25:17.300 --> 00:25:19.940 just means that the cells have to be adjacent, 00:25:19.940 --> 00:25:25.430 or juxtaposed, to each other in order for the sending cell 00:25:25.430 --> 00:25:28.130 to signal to its neighbor, OK? 00:25:28.130 --> 00:25:29.990 So it's not signaling long range, 00:25:29.990 --> 00:25:33.620 but it's signaling to a neighboring cell, OK? 00:25:33.620 --> 00:25:36.770 So now, if we think about this intestinal stem cell, 00:25:36.770 --> 00:25:41.600 one thing intestinal stem cells do as they divide, right? 00:25:41.600 --> 00:25:44.990 So this intestinal stem cell could divide. 00:25:44.990 --> 00:25:47.300 Here is a cell in mitosis. 00:25:47.300 --> 00:25:50.210 It rounds up and divides. 00:25:50.210 --> 00:25:51.920 Here, you still have your paneth cell. 00:25:56.950 --> 00:25:58.960 And then when this cell divides, then it's 00:25:58.960 --> 00:26:02.200 going to be two cells, OK? 00:26:02.200 --> 00:26:06.940 So now, paneth cell, another cell. 00:26:06.940 --> 00:26:08.780 Here the two daughter cells. 00:26:08.780 --> 00:26:11.170 Here's the paneth cell. 00:26:11.170 --> 00:26:14.800 The paneth cell is still secreting this Wnt signal. 00:26:14.800 --> 00:26:17.110 So you have Wnt getting secreted. 00:26:17.110 --> 00:26:19.330 And it's going to signal to its neighbor. 00:26:19.330 --> 00:26:21.940 But this cell is starting to get farther and farther 00:26:21.940 --> 00:26:24.070 away from that signal, right? 00:26:24.070 --> 00:26:26.680 So you can imagine this is happening right here 00:26:26.680 --> 00:26:28.840 in the tissue, where this cell is 00:26:28.840 --> 00:26:31.990 at the boundary of the niche, OK? 00:26:31.990 --> 00:26:34.720 So this cell that gets pushed out of the niche 00:26:34.720 --> 00:26:44.140 is going to start to differentiate, OK? 00:26:44.140 --> 00:26:48.130 Because it's no longer seeing the signal, OK? 00:26:48.130 --> 00:26:50.710 So it's the lack of the Wnt signal 00:26:50.710 --> 00:26:53.530 which tells cells basically that they 00:26:53.530 --> 00:26:56.620 should start differentiating into the various cell 00:26:56.620 --> 00:26:58.160 types of the gut. 00:26:58.160 --> 00:27:00.880 But the cells that are stuck at the base of the crypt, 00:27:00.880 --> 00:27:05.360 down with the paneth cells, are still getting the Wnt signal. 00:27:05.360 --> 00:27:12.730 And so they remain an intestinal stem cell, OK? 00:27:12.730 --> 00:27:15.910 So here is just a diagram showing you part of that. 00:27:15.910 --> 00:27:19.150 So the niche is down here, where you have the stem cells. 00:27:19.150 --> 00:27:21.760 The paneth cells would be some of these blue cells 00:27:21.760 --> 00:27:22.720 at the base. 00:27:22.720 --> 00:27:27.100 But there are also other cells below the epithelial lining 00:27:27.100 --> 00:27:31.630 known as stromal cells that are also secreting Wnt. 00:27:31.630 --> 00:27:34.210 And so this compartment down here 00:27:34.210 --> 00:27:37.720 has high Wnt ligan activity. 00:27:37.720 --> 00:27:42.130 And that tells cells that remain here to stay stem cells. 00:27:42.130 --> 00:27:43.960 But the cells that are getting pushed up 00:27:43.960 --> 00:27:47.170 and moving up towards the lumen, they no longer 00:27:47.170 --> 00:27:48.680 receive this signal. 00:27:48.680 --> 00:27:52.300 And so they are going to start to differentiate, OK? 00:27:52.300 --> 00:27:56.320 So you can think of this system as almost a conveyor 00:27:56.320 --> 00:27:59.320 belt. There's a conveyor belt-like movement of cells 00:27:59.320 --> 00:28:02.610 from the base of the crypt up towards the tip of the villis, 00:28:02.610 --> 00:28:03.310 OK? 00:28:03.310 --> 00:28:06.610 And when the cells move away from the niche cells, 00:28:06.610 --> 00:28:09.940 then they no longer have the self-renewal signal. 00:28:09.940 --> 00:28:12.130 And therefore, they go on to differentiate. 00:28:18.560 --> 00:28:19.060 OK. 00:28:19.060 --> 00:28:20.510 We'll go back for now. 00:28:20.510 --> 00:28:21.010 All right. 00:28:21.010 --> 00:28:25.150 Now, I want to tell you a little bit about this signal, Wnt, 00:28:25.150 --> 00:28:28.990 because it's something that's come up before in the lecture, 00:28:28.990 --> 00:28:30.830 even though you might not know it. 00:28:30.830 --> 00:28:34.270 So Wnt is a ligand. 00:28:34.270 --> 00:28:37.180 So it functions much like a growth factor. 00:28:37.180 --> 00:28:40.540 This is a protein that is secreted from the cell, 00:28:40.540 --> 00:28:43.630 and then binds to receptors on other cells, 00:28:43.630 --> 00:28:48.010 and induces signaling events in those cells, OK? 00:28:48.010 --> 00:28:49.780 And Wnt stands for-- 00:28:49.780 --> 00:28:54.910 the W stands for wingless, OK? 00:28:54.910 --> 00:28:58.120 So you remember from earlier in the semester, 00:28:58.120 --> 00:29:04.180 wingless was identified as a mutant 00:29:04.180 --> 00:29:09.220 that disrupts the formation of wings in the fly, OK? 00:29:09.220 --> 00:29:14.920 So one of the places where these genes were discovered 00:29:14.920 --> 00:29:16.330 is in the fly. 00:29:16.330 --> 00:29:23.230 The nt of Wnt comes from int 1, which 00:29:23.230 --> 00:29:28.540 stands for the integration of mouse mammary virus 1. 00:29:28.540 --> 00:29:31.000 Sorry, that's a little bit more of a mouthful. 00:29:31.000 --> 00:29:34.015 The integration of mouse-- 00:29:36.850 --> 00:29:43.460 actually, sorry, mouse mammary tumor virus 1. 00:29:43.460 --> 00:29:44.920 I forgot the tumor part of it. 00:29:52.590 --> 00:29:53.500 OK. 00:29:53.500 --> 00:29:56.740 So the W in Wnt is from wingless. 00:29:56.740 --> 00:30:01.060 The nt in Wnt is from int 1, OK? 00:30:01.060 --> 00:30:06.190 And so as you can see, there are two different systems 00:30:06.190 --> 00:30:09.210 where this type of gene was discovered. 00:30:09.210 --> 00:30:11.840 They are very disparate from each other. 00:30:11.840 --> 00:30:16.090 One was in a developmental mutant, in the fruit fly. 00:30:16.090 --> 00:30:21.070 The other was in a mouse system, where 00:30:21.070 --> 00:30:24.070 the integration of the virus caused over-expression 00:30:24.070 --> 00:30:28.420 of Wnt, which caused it as tumor genesis, OK? 00:30:28.420 --> 00:30:32.200 So these disparate systems led to the identification 00:30:32.200 --> 00:30:35.350 of this Wnt molecule. 00:30:35.350 --> 00:30:39.310 And this is a defining member of a signaling pathway 00:30:39.310 --> 00:30:42.170 that regulates stem cell renewal. 00:30:42.170 --> 00:30:44.800 And I just want to briefly go through the logic 00:30:44.800 --> 00:30:47.980 of the signaling pathway, because I want 00:30:47.980 --> 00:30:50.860 you to get a sense that not all signaling pathways are 00:30:50.860 --> 00:30:52.840 like Ras-MAP kinase, but there can be 00:30:52.840 --> 00:30:55.450 different regulatory logic, OK? 00:30:55.450 --> 00:30:59.380 So what's the regulatory logic of this pathway? 00:31:03.080 --> 00:31:11.270 So the regulatory logic is shown in this cartoon. 00:31:11.270 --> 00:31:13.570 And I'm going to start with a cell that 00:31:13.570 --> 00:31:15.970 does not see Wnt ligand. 00:31:15.970 --> 00:31:19.270 So that would be the case on the left here. 00:31:19.270 --> 00:31:20.980 So if there's no Wnt ligand-- 00:31:20.980 --> 00:31:24.110 I want you to focus on what's going on here-- 00:31:24.110 --> 00:31:28.420 there's a complex that's present in the cytoplasm of the cell. 00:31:28.420 --> 00:31:30.310 And what it's doing is it's destroying 00:31:30.310 --> 00:31:33.700 this beta-catenin protein, OK? 00:31:33.700 --> 00:31:36.880 So what beta-catenin is-- 00:31:36.880 --> 00:31:41.590 among other things, it's a transcriptional coactivator. 00:31:41.590 --> 00:31:43.345 So it's basically a transcription factor. 00:31:48.580 --> 00:31:52.780 So it works with another protein to regulate the expression 00:31:52.780 --> 00:31:56.720 of certain genes, OK? 00:31:56.720 --> 00:32:01.180 And in the absence of Wnt, this beta-catenin transcription 00:32:01.180 --> 00:32:07.090 factor is destroyed and is not able to get into the nucleus, 00:32:07.090 --> 00:32:09.460 OK? 00:32:09.460 --> 00:32:19.000 So if there's no Wnt, then beta-catenin is destroyed. 00:32:22.390 --> 00:32:24.310 And it's destroyed using a system 00:32:24.310 --> 00:32:26.770 that I introduced in Monday's lecture, which 00:32:26.770 --> 00:32:31.030 is regulated proteolysis by polyubiquitination, OK? 00:32:31.030 --> 00:32:32.390 So the first real-- 00:32:35.050 --> 00:32:42.010 so you have regulated proteolysis 00:32:42.010 --> 00:32:43.790 by polyubiquitination. 00:32:47.200 --> 00:32:50.500 So the way this works, as seen here, 00:32:50.500 --> 00:32:56.620 is that beta-catenin is bound by this complex. 00:32:56.620 --> 00:33:00.250 And there's a kinase that phosphorylates beta-catenin. 00:33:00.250 --> 00:33:02.680 And then the phosphorylated beta-catenin 00:33:02.680 --> 00:33:05.410 recruits this E3 ubiquitin ligase, which 00:33:05.410 --> 00:33:08.320 polyubiquitinates it, OK? 00:33:08.320 --> 00:33:10.670 So that leads to the destruction of beta-catenin 00:33:10.670 --> 00:33:14.230 in the absence of a Wnt signal. 00:33:14.230 --> 00:33:17.020 But when Wnt ligand is around, this 00:33:17.020 --> 00:33:20.980 leads to the disassembly of this complex, which is known 00:33:20.980 --> 00:33:23.110 as the destruction complex. 00:33:23.110 --> 00:33:26.410 And that leads to beta-catenin accumulating. 00:33:26.410 --> 00:33:29.230 And once it accumulates, it goes into the nucleus 00:33:29.230 --> 00:33:32.710 and starts changing gene expression, OK? 00:33:32.710 --> 00:33:45.720 So in the presence of Wnt, beta-catenin is nuclear. 00:33:45.720 --> 00:33:48.640 And that's where it needs to be, if it's going to regulate 00:33:48.640 --> 00:33:51.550 gene expression, OK? 00:33:51.550 --> 00:33:54.580 So what you see is the logic of this pathway 00:33:54.580 --> 00:33:57.880 is you have a double negative, where 00:33:57.880 --> 00:34:03.125 you have a complex, which is known as the destruction 00:34:03.125 --> 00:34:03.625 complex. 00:34:08.219 --> 00:34:10.780 And it includes this gene, APC, which we're 00:34:10.780 --> 00:34:12.790 going to talk about on Friday. 00:34:12.790 --> 00:34:15.909 This destruction complex is inhibiting beta-catenin 00:34:15.909 --> 00:34:16.960 by destroying it. 00:34:21.420 --> 00:34:26.860 And the way that Wnt induces beta-catenin activation 00:34:26.860 --> 00:34:29.830 is by inhibiting the inhibitor. 00:34:29.830 --> 00:34:33.889 So Wnt inhibits the destruction complex, 00:34:33.889 --> 00:34:37.150 which then stabilizes beta-catenin and allows 00:34:37.150 --> 00:34:39.489 it to go to the nucleus, OK? 00:34:39.489 --> 00:34:42.280 So the other piece of the logic here 00:34:42.280 --> 00:34:48.520 is you have inhibition of an inhibitor 00:34:48.520 --> 00:34:50.487 to activate beta-catenin. 00:34:55.469 --> 00:34:57.385 Any questions on the pathway? 00:35:04.210 --> 00:35:04.710 OK. 00:35:04.710 --> 00:35:11.040 So now that we have our intestinal stem cells 00:35:11.040 --> 00:35:16.710 and we have a way, by increasing Wnt in this compartment, 00:35:16.710 --> 00:35:22.500 to maintain the intestinal stem cells through self-renewal, now 00:35:22.500 --> 00:35:25.080 we have to talk about the compensatory 00:35:25.080 --> 00:35:28.260 mechanism of death, which allows this tissue 00:35:28.260 --> 00:35:29.670 to maintain homeostasis. 00:35:34.930 --> 00:35:35.430 OK. 00:35:35.430 --> 00:35:39.870 So death-- in this case, death is going to be useful. 00:35:39.870 --> 00:35:45.430 And the process of death is called apoptosis. 00:35:48.710 --> 00:35:51.600 And apoptosis is Greek for falling off. 00:36:01.430 --> 00:36:03.510 And that's essentially what these cells 00:36:03.510 --> 00:36:07.920 are doing, because the cells, as they 00:36:07.920 --> 00:36:11.280 move from the base of the crypt up towards the lumen-- 00:36:11.280 --> 00:36:12.870 eventually, they're going to fall off 00:36:12.870 --> 00:36:16.630 into the lumen of the intestine. 00:36:16.630 --> 00:36:19.190 So again, I'll draw. 00:36:19.190 --> 00:36:20.205 Here's a villus. 00:36:20.205 --> 00:36:21.080 This is now a villus. 00:36:37.840 --> 00:36:40.980 And so what happens is, at the tip of the villus, 00:36:40.980 --> 00:36:45.060 cells are going to be shed from the lining of the epithelium 00:36:45.060 --> 00:36:46.260 into the lumen. 00:36:46.260 --> 00:36:49.320 The lumen is up here. 00:36:49.320 --> 00:36:50.820 This is the villus. 00:36:50.820 --> 00:36:53.340 And the cells are going to shed off into the lumen 00:36:53.340 --> 00:36:57.750 and be removed from the organ system, OK? 00:36:57.750 --> 00:37:06.060 So cells are shed into the lumen here, OK? 00:37:06.060 --> 00:37:09.420 And this is going to balance the renewal 00:37:09.420 --> 00:37:17.040 at the base of the crypts such that there's homeostasis. 00:37:17.040 --> 00:37:19.290 So I just-- the movie I was showing you 00:37:19.290 --> 00:37:22.590 at the beginning of class was a movie showing you 00:37:22.590 --> 00:37:25.950 what happens to a cell undergoing apoptosis. 00:37:25.950 --> 00:37:29.700 So in this case, the cell is binucleate and unhappy. 00:37:29.700 --> 00:37:34.410 And then you're going to see that it basically explodes, OK? 00:37:34.410 --> 00:37:36.970 So that's a cell undergoing apoptosis. 00:37:36.970 --> 00:37:40.950 But you see that there is a clear change in cell morphology 00:37:40.950 --> 00:37:44.190 and physiology associated with this. 00:37:44.190 --> 00:37:46.590 And I just want to point out that this is also something 00:37:46.590 --> 00:37:49.450 that we talked about earlier in the course. 00:37:49.450 --> 00:37:53.250 And we talked about experiments, a genetic screen that 00:37:53.250 --> 00:37:56.340 led to the identification of the pathway that 00:37:56.340 --> 00:37:58.590 regulates apoptosis. 00:37:58.590 --> 00:38:00.840 And that was done by Robert Horvitz. 00:38:00.840 --> 00:38:05.780 Much of it was done by Robert Horvitz in his lab here at MIT. 00:38:05.780 --> 00:38:10.680 And for that work, Robert Horvitz, in addition to 00:38:10.680 --> 00:38:15.210 his colleagues, won the 2002 Nobel Prize. 00:38:15.210 --> 00:38:17.040 So you'll recall this is something 00:38:17.040 --> 00:38:20.100 we talked about in the context of a genetic screen. 00:38:20.100 --> 00:38:21.720 But this is something that's-- 00:38:21.720 --> 00:38:25.140 this is what it's doing in your intestine system. 00:38:25.140 --> 00:38:29.880 It's balancing renewal so that you have homeostasis. 00:38:29.880 --> 00:38:36.170 So during apoptosis, a cell goes through a series of changes. 00:38:36.170 --> 00:38:38.490 First-- or what happens eventually 00:38:38.490 --> 00:38:42.300 is the nucleus becomes fragmented and chromosomal DNA 00:38:42.300 --> 00:38:43.560 even gets fragmented. 00:38:43.560 --> 00:38:45.600 It gets chopped up. 00:38:45.600 --> 00:38:49.710 And also, the plasma membrane also 00:38:49.710 --> 00:38:54.420 starts to bleb and fragment such that it breaks up 00:38:54.420 --> 00:38:58.470 into what are known as these apoptotic bodies, OK? 00:38:58.470 --> 00:39:01.590 And so you can think of these apoptotic bodies 00:39:01.590 --> 00:39:06.060 as bite-sized pieces of cell that neighboring 00:39:06.060 --> 00:39:11.070 phagocytic cells can eat up and remove them from the body, OK? 00:39:11.070 --> 00:39:13.992 So in this case, the cells are being shed into the lumen. 00:39:13.992 --> 00:39:15.450 So they don't need to get eaten up, 00:39:15.450 --> 00:39:18.900 because they're just going to go out of the digestive tract. 00:39:27.160 --> 00:39:30.310 So there are-- cells have numerous ways 00:39:30.310 --> 00:39:34.270 to activate this apoptosis process. 00:39:34.270 --> 00:39:39.070 I'm going to tell you about two types of signals 00:39:39.070 --> 00:39:44.000 that regulate whether or not a cell undergoes apoptosis. 00:39:49.990 --> 00:39:53.410 The first is that there can be a signal that basically tells 00:39:53.410 --> 00:39:58.480 the cell to kill itself, OK? 00:39:58.480 --> 00:40:00.580 So you can think of this as a kill signal. 00:40:03.920 --> 00:40:07.060 And one type of way to activate this signal 00:40:07.060 --> 00:40:10.930 is if the DNA is irreparably damaged. 00:40:10.930 --> 00:40:15.550 So if there is a high level of DNA damage, 00:40:15.550 --> 00:40:19.870 this induces a signaling process in the cell. 00:40:19.870 --> 00:40:23.740 And one of the results of that signal-- 00:40:23.740 --> 00:40:26.290 in addition to regulating the cell cycle, 00:40:26.290 --> 00:40:29.770 if the DNA damage is great enough, 00:40:29.770 --> 00:40:32.490 it will induce an apoptotic signal. 00:40:32.490 --> 00:40:37.480 And it will activate the pathway that the Horvitz lab elucidated 00:40:37.480 --> 00:40:39.940 in the worm, OK? 00:40:39.940 --> 00:40:41.180 So there's a signal. 00:40:41.180 --> 00:40:45.430 And that leads to apoptosis and death. 00:40:50.110 --> 00:40:54.220 Another type of signal that's critically important for tissue 00:40:54.220 --> 00:40:57.290 homeostasis and determining whether or not cells live 00:40:57.290 --> 00:41:01.690 or die is a survival signal. 00:41:01.690 --> 00:41:03.640 So there are cell survival signals. 00:41:08.950 --> 00:41:13.540 And many of the growth factors, such as EGF which you've heard 00:41:13.540 --> 00:41:14.410 about-- 00:41:14.410 --> 00:41:17.740 in addition to inducing proliferation, 00:41:17.740 --> 00:41:23.230 these growth factors also tell the cell not to die, OK? 00:41:23.230 --> 00:41:25.285 So these could be growth factors. 00:41:30.670 --> 00:41:35.830 And what these cell survival signals do 00:41:35.830 --> 00:41:37.870 is they repress apoptosis. 00:41:41.890 --> 00:41:45.460 And so you can think of it where you have 00:41:45.460 --> 00:41:49.030 a cell constantly needs to be communicated to. 00:41:49.030 --> 00:41:52.660 And it needs to be told don't die, 00:41:52.660 --> 00:41:55.660 don't die, don't die, don't die. 00:41:55.660 --> 00:41:58.330 And then if you remove that signal, 00:41:58.330 --> 00:42:00.340 it won't be getting that information anymore. 00:42:00.340 --> 00:42:03.430 And it can undergo apoptosis, OK? 00:42:03.430 --> 00:42:06.760 So if we were to remove this signal, 00:42:06.760 --> 00:42:09.400 you remove the brakes on apoptosis. 00:42:09.400 --> 00:42:12.520 And the cell will undergo cell death, OK? 00:42:12.520 --> 00:42:17.350 So this ensures that you don't have a cell just kind 00:42:17.350 --> 00:42:19.750 of like going on and doing its own thing, 00:42:19.750 --> 00:42:22.360 because cells, in order to live, often 00:42:22.360 --> 00:42:25.960 need to have some sort of signal from another cell that 00:42:25.960 --> 00:42:27.170 tells them to live. 00:42:27.170 --> 00:42:31.090 And so there's some coordination between cells such 00:42:31.090 --> 00:42:33.400 that you don't have cells rampantly 00:42:33.400 --> 00:42:34.675 dividing out of control. 00:42:40.670 --> 00:42:42.700 Now, the reason we're doing this right 00:42:42.700 --> 00:42:45.460 before we talk about cancer on Friday 00:42:45.460 --> 00:42:48.220 is because everything that I'm telling you 00:42:48.220 --> 00:42:52.450 is really essential to understand how a tumor is 00:42:52.450 --> 00:42:55.380 formed in an organ system, OK? 00:42:55.380 --> 00:42:57.970 And I want to end the lecture by just planting 00:42:57.970 --> 00:43:01.210 a seed of an idea in your heads before we move on 00:43:01.210 --> 00:43:03.940 to talk about cancer on Friday. 00:43:03.940 --> 00:43:07.390 And I want you to think about the organization 00:43:07.390 --> 00:43:13.060 of this system, where you have stem cells undergoing renewal. 00:43:13.060 --> 00:43:17.050 And then the stem cells are just a small fraction 00:43:17.050 --> 00:43:19.120 of the cells in the system. 00:43:19.120 --> 00:43:21.070 And they're dividing slowly, OK? 00:43:21.070 --> 00:43:22.780 So let's think about the stem cells. 00:43:25.880 --> 00:43:29.395 The DNA on the stem cells, these are dividing slowly. 00:43:33.490 --> 00:43:35.230 And because they're dividing slowly, 00:43:35.230 --> 00:43:37.060 they're not going to-- their DNA is not 00:43:37.060 --> 00:43:40.330 going to accumulate as many mutations. 00:43:40.330 --> 00:43:43.060 So there is going to be fewer mutations. 00:43:46.010 --> 00:43:47.630 But these are the cells, and this 00:43:47.630 --> 00:43:53.480 is the genomic DNA that is going to stay with the organ, OK? 00:43:53.480 --> 00:43:57.250 So the stem cells are like the crown jewels of the organ. 00:43:57.250 --> 00:44:00.950 This is the material the organ wants to protect, 00:44:00.950 --> 00:44:03.380 because it's what's going to be lasting 00:44:03.380 --> 00:44:08.060 in the organ the entire lifetime of the organism, OK? 00:44:08.060 --> 00:44:11.750 So you get slow division here and self-renewal. 00:44:11.750 --> 00:44:15.260 And this cell will stay with the organ. 00:44:15.260 --> 00:44:18.200 But then where most of the mitosis and cell division 00:44:18.200 --> 00:44:20.990 happens and replication happens, it 00:44:20.990 --> 00:44:25.640 leads to an expansion of cells that all differentiate. 00:44:25.640 --> 00:44:27.410 And because the cells all differentiate, 00:44:27.410 --> 00:44:31.580 they will all eventually die and get removed from the organ, OK? 00:44:31.580 --> 00:44:36.530 And this is termed transient amplification. 00:44:36.530 --> 00:44:41.270 So when there's transient amplification of one 00:44:41.270 --> 00:44:44.400 of the daughters of this stem cell, 00:44:44.400 --> 00:44:46.025 this is where there's rapid division. 00:44:49.140 --> 00:44:52.180 And where there is rapid replication and division, 00:44:52.180 --> 00:44:54.580 this is where you can get the most mutations. 00:44:58.390 --> 00:45:00.910 But from the standpoint of cancer, 00:45:00.910 --> 00:45:02.800 that doesn't really matter, right? 00:45:02.800 --> 00:45:05.320 Because in order to have a tumor, 00:45:05.320 --> 00:45:07.630 the cells have to stay in the body. 00:45:07.630 --> 00:45:09.490 And so all of these cells are going 00:45:09.490 --> 00:45:11.740 to undergo programmed cell death, 00:45:11.740 --> 00:45:14.230 and then be shed into the lumen of the intestine 00:45:14.230 --> 00:45:18.190 and removed from the organism entirely, OK? 00:45:18.190 --> 00:45:23.020 And so this is actually one important way 00:45:23.020 --> 00:45:28.180 that our organs and our bodies prevent tumors from happening, 00:45:28.180 --> 00:45:32.470 because the cell type that is going to remain in our body 00:45:32.470 --> 00:45:36.460 is the one that's protected from accumulating mutations, OK? 00:45:36.460 --> 00:45:38.770 And we'll come back to this on Friday. 00:45:38.770 --> 00:45:40.660 And so I will see you on Friday. 00:45:40.660 --> 00:45:45.480 And we'll talk about cancer on Friday.