1 00:00:16,412 --> 00:00:17,370 ADAM MARTIN: All right. 2 00:00:17,370 --> 00:00:20,580 So in Monday's lecture, we talked 3 00:00:20,580 --> 00:00:27,540 about how cells replicate, OK? 4 00:00:27,540 --> 00:00:32,880 And today, I want to talk about how now an entire organ would 5 00:00:32,880 --> 00:00:34,380 essentially replicate. 6 00:00:34,380 --> 00:00:36,540 In this case, it's not going to divide, 7 00:00:36,540 --> 00:00:42,240 but it's going to regenerate or renew itself, OK? 8 00:00:42,240 --> 00:00:50,400 And so this involves adult stem cells and also apoptosis , 9 00:00:50,400 --> 00:00:53,580 which you've heard a little bit about earlier in the course. 10 00:00:53,580 --> 00:00:57,450 And to explain this to you, I'm going to have basically a model 11 00:00:57,450 --> 00:00:59,250 organ that we'll use. 12 00:00:59,250 --> 00:01:02,490 And we'll use it for a couple lectures. 13 00:01:02,490 --> 00:01:07,020 And the model organ is going to be the lining of the intestine, 14 00:01:07,020 --> 00:01:08,070 OK? 15 00:01:08,070 --> 00:01:16,470 So the lining of the intestine is an epithelial tissue. 16 00:01:16,470 --> 00:01:19,160 And I'll tell you a little bit about epithelia 17 00:01:19,160 --> 00:01:20,490 in just a minute. 18 00:01:20,490 --> 00:01:24,220 But you have the intestinal epithelium. 19 00:01:24,220 --> 00:01:27,120 And this is the-- these are the cells that 20 00:01:27,120 --> 00:01:30,170 are the lining of the intestine, OK? 21 00:01:30,170 --> 00:01:34,170 And one of the reasons that I've chosen this system 22 00:01:34,170 --> 00:01:37,710 is because the lining of your intestine 23 00:01:37,710 --> 00:01:42,150 has pretty remarkable regenerative capabilities, OK? 24 00:01:42,150 --> 00:01:56,230 So your small intestine renews about every four to five days, 25 00:01:56,230 --> 00:01:56,730 OK? 26 00:01:56,730 --> 00:02:01,560 So the vast majority of your cells in the intestine 27 00:02:01,560 --> 00:02:05,820 were basically derived in the last four to five days, OK? 28 00:02:05,820 --> 00:02:11,550 So humans aren't as cool as some organisms, 29 00:02:11,550 --> 00:02:14,460 like newts, in that you can't cut off your arm 30 00:02:14,460 --> 00:02:15,810 and have it grow back. 31 00:02:15,810 --> 00:02:17,590 But at least we have the intestine, 32 00:02:17,590 --> 00:02:22,380 which undergoes a pretty dramatic regeneration, OK? 33 00:02:22,380 --> 00:02:24,330 And this is not-- 34 00:02:24,330 --> 00:02:26,790 the intestine is unique in how rapid this is. 35 00:02:26,790 --> 00:02:30,990 But you have other tissues that also exhibit continual renewal, 36 00:02:30,990 --> 00:02:33,990 like your skin and your blood cells. 37 00:02:33,990 --> 00:02:35,760 And even the cells of your that line 38 00:02:35,760 --> 00:02:39,150 your insides of your lungs, they do exhibit renewal 39 00:02:39,150 --> 00:02:41,090 capabilities, OK? 40 00:02:41,090 --> 00:02:45,090 And so I'm going to use the intestine as a model system. 41 00:02:45,090 --> 00:02:47,850 It doesn't mean it doesn't happen in other tissues. 42 00:02:47,850 --> 00:02:50,040 But it just happens that we can-- 43 00:02:50,040 --> 00:02:53,220 we really understand the intestine system 44 00:02:53,220 --> 00:02:55,620 maybe a little bit more than many other systems. 45 00:02:55,620 --> 00:02:59,170 So I'm going to use it as an example. 46 00:02:59,170 --> 00:03:02,490 So in thinking about the lining of your intestine, 47 00:03:02,490 --> 00:03:06,160 it's important, and it has important functions. 48 00:03:06,160 --> 00:03:08,130 One important function of this lining 49 00:03:08,130 --> 00:03:12,630 is it has to absorb nutrients from food going 50 00:03:12,630 --> 00:03:16,890 through your intestine, OK? 51 00:03:16,890 --> 00:03:26,560 So it exhibits a nutrient absorption function. 52 00:03:26,560 --> 00:03:30,660 Now, the lining of your intimate intestine, much like your skin, 53 00:03:30,660 --> 00:03:34,740 is also a barrier between the inside of your body 54 00:03:34,740 --> 00:03:36,410 and the outside world, right? 55 00:03:36,410 --> 00:03:40,080 Because basically, the inside of your intestine 56 00:03:40,080 --> 00:03:42,810 is contiguous with the outside world, right? 57 00:03:42,810 --> 00:03:45,120 If you open your mouth, you can get down 58 00:03:45,120 --> 00:03:48,000 to the inside of your intestine, OK? 59 00:03:48,000 --> 00:03:51,145 So it serves also an important barrier function. 60 00:03:57,190 --> 00:04:01,810 And one point I want to make about this system right now 61 00:04:01,810 --> 00:04:05,590 is that the intestinal epithelium, like many 62 00:04:05,590 --> 00:04:10,690 of your other organs, are composed of multiple cell 63 00:04:10,690 --> 00:04:12,490 types, OK? 64 00:04:12,490 --> 00:04:17,020 So it also has multiple cell types. 65 00:04:26,190 --> 00:04:26,690 OK. 66 00:04:26,690 --> 00:04:30,230 So let's now consider the lining of the intestine. 67 00:04:30,230 --> 00:04:36,140 And the way the intestine morphologically looks 68 00:04:36,140 --> 00:04:40,850 is that there are a series of invaginations. 69 00:04:40,850 --> 00:04:44,270 So this is a cross-section view through the intestine. 70 00:04:44,270 --> 00:04:47,300 So you have to imagine that this is a cross-section view, 71 00:04:47,300 --> 00:04:49,460 but that this is a plane. 72 00:04:49,460 --> 00:04:54,260 And it's a plane with a lot of invaginations in the plane, 73 00:04:54,260 --> 00:04:56,970 but also protrusions out of the plane. 74 00:04:56,970 --> 00:04:58,365 And so you have to remember-- 75 00:04:58,365 --> 00:04:59,990 you have to think of this as a surface. 76 00:04:59,990 --> 00:05:02,600 And then it's wrapped up into a tube, OK? 77 00:05:02,600 --> 00:05:05,780 So this is just a very simple cross-section image 78 00:05:05,780 --> 00:05:09,800 of the intestine, OK? 79 00:05:09,800 --> 00:05:13,430 And the lining of the intestine is a sheet of cells. 80 00:05:16,500 --> 00:05:21,330 So this lining is composed of many, many cells. 81 00:05:21,330 --> 00:05:23,270 They're columnar in morphology. 82 00:05:29,970 --> 00:05:32,420 So what I've drawn here is just a small section 83 00:05:32,420 --> 00:05:33,900 of the intestine. 84 00:05:33,900 --> 00:05:37,160 This would be the lumen, out here. 85 00:05:37,160 --> 00:05:41,420 This is where the food is, or the food 86 00:05:41,420 --> 00:05:44,390 going through your intestine would be. 87 00:05:44,390 --> 00:05:51,860 And then below here, this is interstitial fluid inside 88 00:05:51,860 --> 00:05:57,530 of your body basically, interstitial, OK? 89 00:05:57,530 --> 00:05:58,700 So the food's up here. 90 00:05:58,700 --> 00:06:01,880 The rest of your body is down here. 91 00:06:01,880 --> 00:06:04,940 And you can see that there are there 92 00:06:04,940 --> 00:06:06,110 there's a structure to it. 93 00:06:06,110 --> 00:06:08,750 It's not just a flat surface that's wrapped up, 94 00:06:08,750 --> 00:06:10,970 but there are invaginations. 95 00:06:10,970 --> 00:06:18,640 And the invaginations are known as intestinal crypts, right? 96 00:06:18,640 --> 00:06:22,180 Much like you would-- 97 00:06:22,180 --> 00:06:26,770 if you bury something, like a body, it would go below ground. 98 00:06:26,770 --> 00:06:31,990 So the crypt is below the surface of the lumen. 99 00:06:31,990 --> 00:06:37,780 And this these projections, out here, are known as villi. 100 00:06:37,780 --> 00:06:40,420 So they're the villi of your gut, OK? 101 00:06:43,890 --> 00:06:47,000 Now, if we consider-- 102 00:06:47,000 --> 00:06:49,770 and this lining is made up of multiple cell 103 00:06:49,770 --> 00:06:51,750 types, which I've outlined up here 104 00:06:51,750 --> 00:06:53,100 and which are in your handout. 105 00:06:53,100 --> 00:06:54,870 So you don't have to write these down. 106 00:06:54,870 --> 00:06:56,340 But this is just making the point 107 00:06:56,340 --> 00:06:59,380 that there are various differentiated cell types. 108 00:06:59,380 --> 00:07:02,190 There are enterocytes, which are the absorptive cells. 109 00:07:02,190 --> 00:07:04,410 These are the cells that are taking in nutrients 110 00:07:04,410 --> 00:07:07,070 and transporting them into your body. 111 00:07:07,070 --> 00:07:09,780 There are enteroendocrine cells that 112 00:07:09,780 --> 00:07:12,780 play an important signaling function in the gut to regulate 113 00:07:12,780 --> 00:07:15,110 the biology of the gut system. 114 00:07:15,110 --> 00:07:17,970 There are a goblet cells, which secrete mucus 115 00:07:17,970 --> 00:07:22,230 into the intestine system, which protects these epithelial cells 116 00:07:22,230 --> 00:07:26,400 from digestive enzymes that are present in the lumen. 117 00:07:26,400 --> 00:07:29,910 And there is this last cell type, the paneth cell, 118 00:07:29,910 --> 00:07:33,750 which functions as an important role in regulating stem cells, 119 00:07:33,750 --> 00:07:36,310 as I'll outline in just a minute. 120 00:07:36,310 --> 00:07:39,570 So these are all the differentiated cell types. 121 00:07:39,570 --> 00:07:41,760 But there's a type of cell that's 122 00:07:41,760 --> 00:07:44,040 an undifferentiated cell type. 123 00:07:44,040 --> 00:07:46,720 And that's the intestinal stem cell, 124 00:07:46,720 --> 00:07:50,260 which will be the hero of today's lecture. 125 00:07:50,260 --> 00:07:50,760 All right. 126 00:07:50,760 --> 00:07:55,740 Now, if we consider just a small group of cells, 127 00:07:55,740 --> 00:07:59,040 what these cells look like is this, OK? 128 00:07:59,040 --> 00:08:03,350 So these are what are known as epithelial cells. 129 00:08:03,350 --> 00:08:07,780 And epithelial cells have certain properties. 130 00:08:07,780 --> 00:08:11,250 The first is you see that this end of the epithelial cell 131 00:08:11,250 --> 00:08:14,070 looks different from this end, OK? 132 00:08:14,070 --> 00:08:18,810 And this is called an apical-basal polarity. 133 00:08:23,670 --> 00:08:26,050 So much like neurons have a polarity where 134 00:08:26,050 --> 00:08:28,830 the on one side of the neuron there are dendrites 135 00:08:28,830 --> 00:08:31,720 and on the other side of the neuron there's an axon, 136 00:08:31,720 --> 00:08:34,530 these cells have another type of polarity, which is 137 00:08:34,530 --> 00:08:37,090 called apical-basal polarity. 138 00:08:37,090 --> 00:08:40,500 So the side facing the lumen is apical. 139 00:08:40,500 --> 00:08:42,840 So the lumen would be up here. 140 00:08:42,840 --> 00:08:46,590 And the basal side would be down here, OK? 141 00:08:46,590 --> 00:08:52,790 So this is basically oriented along this axis of the tissue, 142 00:08:52,790 --> 00:08:53,510 OK? 143 00:08:53,510 --> 00:08:58,920 where apical is on this side, basal is on this side, OK? 144 00:08:58,920 --> 00:09:03,990 And these projections from the individual cell, these 145 00:09:03,990 --> 00:09:08,040 are called microvilli. 146 00:09:08,040 --> 00:09:10,620 And essentially, these plasma membrane 147 00:09:10,620 --> 00:09:13,860 corrugations increase the surface area 148 00:09:13,860 --> 00:09:18,840 through which nutrients can be absorbed into these cells, OK? 149 00:09:18,840 --> 00:09:23,370 Now, one other defining feature of these cells 150 00:09:23,370 --> 00:09:26,170 is they have proteins that protrude from the plasma 151 00:09:26,170 --> 00:09:26,670 membrane. 152 00:09:31,420 --> 00:09:35,950 And these are adhesion proteins that couple the cells together. 153 00:09:35,950 --> 00:09:37,780 And actually, the cells are stuck together 154 00:09:37,780 --> 00:09:40,210 much tighter than I'm drawing here, such 155 00:09:40,210 --> 00:09:42,640 that the cells form a barrier so that things 156 00:09:42,640 --> 00:09:47,530 can pass unregulated from the lumen into the body, OK? 157 00:09:47,530 --> 00:09:50,260 But these proteins, which I'm drawing 158 00:09:50,260 --> 00:09:52,930 sticking out of the membranes of the cells, 159 00:09:52,930 --> 00:09:53,950 are adhesion proteins. 160 00:10:00,560 --> 00:10:03,220 And these adhesion proteins simply 161 00:10:03,220 --> 00:10:06,160 link the cells together such that they form 162 00:10:06,160 --> 00:10:09,370 a sheet of cells or tissue. 163 00:10:09,370 --> 00:10:16,490 So they link cells together, OK? 164 00:10:16,490 --> 00:10:20,830 So these are two of the key properties of epithelia. 165 00:10:20,830 --> 00:10:23,200 They have an apical-basal polarity. 166 00:10:23,200 --> 00:10:26,230 And they also exhibit cell-to-cell adhesion, 167 00:10:26,230 --> 00:10:29,560 such as the cells reach out and connect to each other. 168 00:10:29,560 --> 00:10:32,890 And they basically are glued together, or Velcroed together 169 00:10:32,890 --> 00:10:34,990 such that they don't easily come apart. 170 00:10:39,170 --> 00:10:39,670 OK. 171 00:10:39,670 --> 00:10:42,760 Now, in considering this system, what I'm going to tell 172 00:10:42,760 --> 00:10:47,890 you is that there is renewal of this lining. 173 00:10:47,890 --> 00:10:53,723 And the renewal starts at the base of the crypts, OK? 174 00:10:53,723 --> 00:10:55,015 So there's going to be renewal. 175 00:10:57,610 --> 00:11:05,320 And this cell renewal is at the base of the crypts, right? 176 00:11:05,320 --> 00:11:07,020 There are many of these crypts, right? 177 00:11:07,020 --> 00:11:08,840 You have you have like the surface, 178 00:11:08,840 --> 00:11:11,260 but there are many, many invaginations 179 00:11:11,260 --> 00:11:15,000 that are present in your gut. 180 00:11:15,000 --> 00:11:20,890 And the renewal is happening at the base of these crypts, OK? 181 00:11:20,890 --> 00:11:23,950 And that's because at the base of these crypts 182 00:11:23,950 --> 00:11:30,460 are where a type of cell, known as intestinal stem cells, lie, 183 00:11:30,460 --> 00:11:31,600 OK? 184 00:11:31,600 --> 00:11:33,970 So it's at the base of these crypts 185 00:11:33,970 --> 00:11:38,470 where there are what are known as intestinal stem cells. 186 00:11:41,740 --> 00:11:45,070 And I'm going to abbreviate these ISCs for this, 187 00:11:45,070 --> 00:11:47,980 so I don't have to write out intestinal stem cell 188 00:11:47,980 --> 00:11:51,490 whenever I tell you about them, OK? 189 00:11:51,490 --> 00:11:53,530 Now, that's where renewal occurs. 190 00:11:53,530 --> 00:11:57,070 And if you just had more and more cells getting 191 00:11:57,070 --> 00:12:00,970 put in the system without any removal of cells, 192 00:12:00,970 --> 00:12:03,700 then the organ would get bigger and bigger, right? 193 00:12:03,700 --> 00:12:06,490 And so our intestine more or less 194 00:12:06,490 --> 00:12:10,490 staying the same size at this point in our life. 195 00:12:10,490 --> 00:12:18,130 And so in addition to renewal, there's also cell death. 196 00:12:18,130 --> 00:12:21,130 And what happens when cell death occurs 197 00:12:21,130 --> 00:12:24,430 is that cells are shed from the intestinal lining 198 00:12:24,430 --> 00:12:26,000 into the lumen. 199 00:12:26,000 --> 00:12:31,765 So cells are shed into the lumen. 200 00:12:35,870 --> 00:12:39,280 And then they just go with the rest of the crap that's 201 00:12:39,280 --> 00:12:40,660 in your intestinal lumen. 202 00:12:40,660 --> 00:12:45,100 And it's eventually removed from the body, OK? 203 00:12:45,100 --> 00:12:49,930 So some cells are leaving the tissue and going into the lumen 204 00:12:49,930 --> 00:12:54,670 after they've existed for a few days in the intestine, OK? 205 00:12:54,670 --> 00:12:58,960 So to have an organ then the constant size 206 00:12:58,960 --> 00:13:03,350 renewal has to essentially be more or less equal to death, 207 00:13:03,350 --> 00:13:03,850 OK? 208 00:13:03,850 --> 00:13:07,510 And so you can think of this as a type of homeostatic state 209 00:13:07,510 --> 00:13:12,550 for this tissue where, if renewal equals death, you have 210 00:13:12,550 --> 00:13:18,580 what is known as tissue homeostasis, where 211 00:13:18,580 --> 00:13:21,730 the number of cells in the system as a whole 212 00:13:21,730 --> 00:13:25,180 is basically remaining the same, even though there's constantly 213 00:13:25,180 --> 00:13:27,740 new cells going into this system. 214 00:13:27,740 --> 00:13:29,140 But then the cells are also-- 215 00:13:29,140 --> 00:13:31,530 the older cells are being removed from the system. 216 00:13:38,380 --> 00:13:41,230 So what's really key in this process 217 00:13:41,230 --> 00:13:43,420 are these intestinal stem cells. 218 00:13:43,420 --> 00:13:47,200 So I'm first going to tell you about stem cells. 219 00:13:47,200 --> 00:13:55,680 And these are what I would define as adult stem cells, OK? 220 00:13:55,680 --> 00:13:58,330 So they're stem cells that are associated 221 00:13:58,330 --> 00:14:01,000 with a particular organ, OK? 222 00:14:01,000 --> 00:14:02,770 And I want to differentiate this right 223 00:14:02,770 --> 00:14:06,730 now between these types of stem cells 224 00:14:06,730 --> 00:14:08,950 and another type of stem cell that we're 225 00:14:08,950 --> 00:14:11,530 going to talk about later in the course, which 226 00:14:11,530 --> 00:14:13,120 is an embryonic stem cell. 227 00:14:19,620 --> 00:14:22,150 So adult stem cells-- 228 00:14:22,150 --> 00:14:27,420 these stem cells, like intestinal stem cells, 229 00:14:27,420 --> 00:14:34,665 are associated with a specific organ. 230 00:14:39,210 --> 00:14:42,420 And they only give rise to cell types that 231 00:14:42,420 --> 00:14:45,300 are present in that organ, OK? 232 00:14:45,300 --> 00:14:50,050 So they're not-- they can't give rise to any type of cell type. 233 00:14:50,050 --> 00:14:53,880 Your adult stem cells are really specific-- organ-specific, 234 00:14:53,880 --> 00:14:55,200 we'll say. 235 00:14:55,200 --> 00:15:00,000 In contrast, embryonic stem cells are-- 236 00:15:00,000 --> 00:15:03,520 these stem cells have more possibilities. 237 00:15:03,520 --> 00:15:06,270 They can give rise to pretty much any cell 238 00:15:06,270 --> 00:15:09,180 type in an entire organism, OK? 239 00:15:09,180 --> 00:15:11,280 So you can think of these adult stem cells 240 00:15:11,280 --> 00:15:14,790 as being more restricted in their fates 241 00:15:14,790 --> 00:15:17,260 than the embryonic stem cells. 242 00:15:17,260 --> 00:15:21,660 And so what adult stem cells are called 243 00:15:21,660 --> 00:15:26,190 is they're called multipotent, because they can give rise 244 00:15:26,190 --> 00:15:28,630 to multiple different cell types, 245 00:15:28,630 --> 00:15:30,690 but not all of the cell types that are 246 00:15:30,690 --> 00:15:33,000 present in an organism, right? 247 00:15:33,000 --> 00:15:36,570 An intestinal stem cell will not be giving rise 248 00:15:36,570 --> 00:15:42,490 to a blood cell or other cell types in other organs, right? 249 00:15:42,490 --> 00:15:44,880 It's restricted to just giving rise 250 00:15:44,880 --> 00:15:47,910 to cells that are present in that organ. 251 00:15:47,910 --> 00:15:50,460 In contrast, embryonic stem cells 252 00:15:50,460 --> 00:15:56,280 are what are known as totipotent, or sometimes 253 00:15:56,280 --> 00:16:00,810 pluripotent, where this type of cell 254 00:16:00,810 --> 00:16:04,440 really is capable of making any type of cell that 255 00:16:04,440 --> 00:16:08,370 is present in an adult organism, OK? 256 00:16:08,370 --> 00:16:11,400 So that's less restricted than the adult stem cells. 257 00:16:11,400 --> 00:16:14,100 And we're going to come back to these embryonic stem cells 258 00:16:14,100 --> 00:16:16,270 towards the end of the course. 259 00:16:16,270 --> 00:16:19,710 But for understanding cancer and also 260 00:16:19,710 --> 00:16:22,320 tissue homeostasis in the intestine, 261 00:16:22,320 --> 00:16:24,930 we're really needing to focus on the adult stem cells. 262 00:16:28,300 --> 00:16:28,800 OK. 263 00:16:28,800 --> 00:16:32,620 So these adult stem cells have two key properties. 264 00:16:32,620 --> 00:16:34,710 The first is what I just said. 265 00:16:34,710 --> 00:16:35,850 They're multipotent. 266 00:16:41,500 --> 00:16:43,830 And what multipotent means is that they 267 00:16:43,830 --> 00:16:48,510 can give rise to multiple different cell types. 268 00:16:48,510 --> 00:16:54,645 So this stem cell gives rise to multiple cell types. 269 00:17:00,270 --> 00:17:03,420 And this is associated usually with a single organ system. 270 00:17:10,619 --> 00:17:11,119 OK. 271 00:17:11,119 --> 00:17:14,760 So in the case of the intestinal stem cell, 272 00:17:14,760 --> 00:17:18,119 the intestinal stem cell is multipotent. 273 00:17:18,119 --> 00:17:20,490 And it can give rise to many different terminally 274 00:17:20,490 --> 00:17:22,480 differentiated cells. 275 00:17:22,480 --> 00:17:25,890 And you can see here I've just written in example cell types 276 00:17:25,890 --> 00:17:28,349 that the intestinal cell could generate. 277 00:17:28,349 --> 00:17:31,140 It can generate any of the four different types of cells 278 00:17:31,140 --> 00:17:35,850 that I introduced to you at the beginning of the lecture. 279 00:17:35,850 --> 00:17:38,850 The other key aspect of this system 280 00:17:38,850 --> 00:17:41,010 is that, in addition to generating 281 00:17:41,010 --> 00:17:43,740 all of these different cell types, 282 00:17:43,740 --> 00:17:47,610 the stem cell can also renew itself, OK? 283 00:17:47,610 --> 00:17:51,810 So the other key property is this self-renewal. 284 00:17:56,230 --> 00:18:05,280 So the intestinal stem cell also gives rise 285 00:18:05,280 --> 00:18:10,200 to another intestinal stem cell. 286 00:18:10,200 --> 00:18:13,260 So it basically duplicates itself such 287 00:18:13,260 --> 00:18:16,620 that you still have a stem cell in the organ. 288 00:18:16,620 --> 00:18:19,830 And then one of the daughter cells 289 00:18:19,830 --> 00:18:23,080 is self-renewed and remains a stem cell. 290 00:18:23,080 --> 00:18:26,640 The other daughter cell can go on to divide 291 00:18:26,640 --> 00:18:30,780 further and give rise to these differentiated cell types, OK? 292 00:18:39,000 --> 00:18:39,500 All right. 293 00:18:39,500 --> 00:18:41,660 So one question you might be asking 294 00:18:41,660 --> 00:18:45,860 yourself is, how is it that-- 295 00:18:45,860 --> 00:18:49,160 what regulates whether or not a cell 296 00:18:49,160 --> 00:18:52,370 will go on to differentiate or whether it 297 00:18:52,370 --> 00:18:56,780 will stay a stem cell? 298 00:18:56,780 --> 00:18:59,300 And the answer to this question involves 299 00:18:59,300 --> 00:19:01,520 communication between this stem cell 300 00:19:01,520 --> 00:19:05,480 and other cells in the system. 301 00:19:05,480 --> 00:19:09,110 And it involves a special type of cell 302 00:19:09,110 --> 00:19:11,810 called a stem cell niche cell. 303 00:19:11,810 --> 00:19:14,900 And so I'm going to tell you about a model, which 304 00:19:14,900 --> 00:19:17,210 is the stem cell niche model. 305 00:19:17,210 --> 00:19:19,445 And what the stem cell niche model is, 306 00:19:19,445 --> 00:19:23,870 is that basically there is a niche or compartment which 307 00:19:23,870 --> 00:19:28,490 promotes the self-renewal of cells in that compartment that 308 00:19:28,490 --> 00:19:30,300 makes them stem cells. 309 00:19:30,300 --> 00:19:36,890 So the stem cell niche you can think of as a compartment where 310 00:19:36,890 --> 00:19:43,070 signals, similar to the types of signals that we've been talking 311 00:19:43,070 --> 00:19:46,220 about over the past four or five lectures, 312 00:19:46,220 --> 00:19:49,940 regulate the behavior of the cell to ensure self-renewal 313 00:19:49,940 --> 00:19:53,420 and to suppress differentiation, so a compartment 314 00:19:53,420 --> 00:19:58,625 where signals promote stem cell renewal. 315 00:20:09,550 --> 00:20:13,360 I want to ask you one question before I move on, which 316 00:20:13,360 --> 00:20:15,970 is, how would you define-- 317 00:20:15,970 --> 00:20:17,980 how would you determine that there 318 00:20:17,980 --> 00:20:20,860 is a special type of cell that gives rise to all 319 00:20:20,860 --> 00:20:24,280 of the cells in an organ? 320 00:20:24,280 --> 00:20:29,740 If you were tasked with finding this and determining 321 00:20:29,740 --> 00:20:32,650 whether this was true or not, how might you do it? 322 00:20:32,650 --> 00:20:35,980 Does anyone have an idea of what experiment they would do, 323 00:20:35,980 --> 00:20:40,300 or what criteria they would have to determine whether or not 324 00:20:40,300 --> 00:20:41,140 this is a case? 325 00:20:49,990 --> 00:20:53,140 Let's say I gave you a cell, right? 326 00:20:53,140 --> 00:20:54,910 In a dish. 327 00:20:54,910 --> 00:20:57,850 And I asked you to tell me whether or not 328 00:20:57,850 --> 00:21:01,450 you would think this is a stem cell or not. 329 00:21:01,450 --> 00:21:03,795 Yes, miles? 330 00:21:03,795 --> 00:21:09,500 AUDIENCE: [INAUDIBLE] 331 00:21:09,500 --> 00:21:10,586 ADAM MARTIN: Mm-hmm. 332 00:21:10,586 --> 00:21:13,051 AUDIENCE: One cell is produced by the same cell, 333 00:21:13,051 --> 00:21:16,995 assuming that it's not a stem cell 334 00:21:16,995 --> 00:21:25,637 but if the cell [INAUDIBLE] it's a stem cell. 335 00:21:25,637 --> 00:21:26,470 ADAM MARTIN: Mm-hmm. 336 00:21:26,470 --> 00:21:30,580 So Miles suggested he would like to take the cell that I just 337 00:21:30,580 --> 00:21:34,780 gifted him, and let it grow up, and determine whether it gives 338 00:21:34,780 --> 00:21:37,000 rise to multiple cell types. 339 00:21:37,000 --> 00:21:39,370 And Miles said that, if it just gave rise 340 00:21:39,370 --> 00:21:41,500 to a single cell type, that would suggest 341 00:21:41,500 --> 00:21:43,310 that it's not a stem cell. 342 00:21:43,310 --> 00:21:46,690 But if it gave rise to multiple cell types, 343 00:21:46,690 --> 00:21:49,450 then it could be a stem cell, OK? 344 00:21:49,450 --> 00:21:53,110 And it's this type of experiment that-- 345 00:21:53,110 --> 00:21:55,480 this type of experiment has been done, 346 00:21:55,480 --> 00:22:00,160 where you can take an intestine from mice, 347 00:22:00,160 --> 00:22:02,770 and even you can take tissue from humans, 348 00:22:02,770 --> 00:22:05,480 and you can associate the cells from each other 349 00:22:05,480 --> 00:22:09,520 so that you're left with single cells that are separate. 350 00:22:09,520 --> 00:22:13,030 And you can then use some type of flow cytometry 351 00:22:13,030 --> 00:22:14,710 to separate cells. 352 00:22:14,710 --> 00:22:16,900 And you might be interested in a cell that 353 00:22:16,900 --> 00:22:20,260 maybe expresses some marker that you're interested in. 354 00:22:20,260 --> 00:22:23,710 And you can separate those cells and isolate them. 355 00:22:23,710 --> 00:22:26,530 And then you can take an individual cell 356 00:22:26,530 --> 00:22:29,200 and grow it in a dish, OK? 357 00:22:29,200 --> 00:22:32,840 And this has been done for intestinal stem cells. 358 00:22:32,840 --> 00:22:35,590 And if you take an intestinal stem cell 359 00:22:35,590 --> 00:22:38,140 and you grow it in a dish, it can grow up 360 00:22:38,140 --> 00:22:40,780 and form a bulk of tissue. 361 00:22:40,780 --> 00:22:44,650 But what's really remarkable about the result 362 00:22:44,650 --> 00:22:48,100 of this experiment is that, from a stem cell, 363 00:22:48,100 --> 00:22:50,290 you get this massive tissue. 364 00:22:50,290 --> 00:22:53,380 But it self--organizes into a structure that very much 365 00:22:53,380 --> 00:22:59,150 resembles a normal gut, meaning that there are crypts where 366 00:22:59,150 --> 00:23:01,740 the stem cells are localized. 367 00:23:01,740 --> 00:23:03,490 And then if you look at the different cell 368 00:23:03,490 --> 00:23:06,580 types in this, what's known as an organoid, 369 00:23:06,580 --> 00:23:10,570 you see all of the different cell types that are normally 370 00:23:10,570 --> 00:23:12,850 present in the gut, OK? 371 00:23:12,850 --> 00:23:16,090 And so this is an example of a type of experiment 372 00:23:16,090 --> 00:23:19,150 that's done to show whether or not 373 00:23:19,150 --> 00:23:22,780 a certain cell has the capability of functioning 374 00:23:22,780 --> 00:23:24,190 like a stem cell, OK? 375 00:23:24,190 --> 00:23:26,080 So if you start with a stem cell, 376 00:23:26,080 --> 00:23:30,820 you can regenerate the entire organ system essentially. 377 00:23:30,820 --> 00:23:34,360 You might also be familiar with bone marrow transplants. 378 00:23:34,360 --> 00:23:39,760 And so if you kill all the hematopoietic stem cells 379 00:23:39,760 --> 00:23:42,460 in, let's say, a mouse, then you can 380 00:23:42,460 --> 00:23:45,700 transplant in a single hematopoietic stem cell 381 00:23:45,700 --> 00:23:46,870 into that system. 382 00:23:46,870 --> 00:23:52,990 And it will regenerate all the blood cells in that system, OK? 383 00:23:52,990 --> 00:23:57,010 So those are just a few examples of how one might functionally 384 00:23:57,010 --> 00:23:59,860 define a stem cell in an experimental setting. 385 00:24:02,480 --> 00:24:02,980 All right. 386 00:24:02,980 --> 00:24:06,190 So now, I want to tell you about the types of signals 387 00:24:06,190 --> 00:24:09,960 and how these signals are promoting stem cell renewal, 388 00:24:09,960 --> 00:24:10,630 OK? 389 00:24:10,630 --> 00:24:13,720 So in this case, the niche, stem cell niche 390 00:24:13,720 --> 00:24:14,920 is going to be right here. 391 00:24:17,910 --> 00:24:20,020 And the types of signals involved-- 392 00:24:20,020 --> 00:24:23,440 I'll just draw some cells here. 393 00:24:23,440 --> 00:24:26,230 One of the types of cells that's part 394 00:24:26,230 --> 00:24:29,440 of the niche in the intestine is the cell type 395 00:24:29,440 --> 00:24:31,705 that I introduced you as the paneth cell. 396 00:24:34,360 --> 00:24:38,230 And these paneth cells localized to the base of the crypts 397 00:24:38,230 --> 00:24:41,230 together with the intestinal stem cells. 398 00:24:41,230 --> 00:24:44,950 And what paneth cells do is they send a signal 399 00:24:44,950 --> 00:24:46,960 to neighboring cells. 400 00:24:46,960 --> 00:24:49,420 And this signal is a Wnt signal, which I'll tell you 401 00:24:49,420 --> 00:24:51,050 about in just a minute. 402 00:24:51,050 --> 00:24:54,100 And so this is the intestinal stem cell here. 403 00:24:54,100 --> 00:24:58,660 And the paneth cell is signaling to that intestinal stem cell 404 00:24:58,660 --> 00:25:02,950 through a secreted ligand known as Wnt. 405 00:25:02,950 --> 00:25:04,870 So Wnt is a secreted ligand. 406 00:25:08,600 --> 00:25:17,300 And this signal is what's known as a juxtacrine signal, which 407 00:25:17,300 --> 00:25:19,940 just means that the cells have to be adjacent, 408 00:25:19,940 --> 00:25:25,430 or juxtaposed, to each other in order for the sending cell 409 00:25:25,430 --> 00:25:28,130 to signal to its neighbor, OK? 410 00:25:28,130 --> 00:25:29,990 So it's not signaling long range, 411 00:25:29,990 --> 00:25:33,620 but it's signaling to a neighboring cell, OK? 412 00:25:33,620 --> 00:25:36,770 So now, if we think about this intestinal stem cell, 413 00:25:36,770 --> 00:25:41,600 one thing intestinal stem cells do as they divide, right? 414 00:25:41,600 --> 00:25:44,990 So this intestinal stem cell could divide. 415 00:25:44,990 --> 00:25:47,300 Here is a cell in mitosis. 416 00:25:47,300 --> 00:25:50,210 It rounds up and divides. 417 00:25:50,210 --> 00:25:51,920 Here, you still have your paneth cell. 418 00:25:56,950 --> 00:25:58,960 And then when this cell divides, then it's 419 00:25:58,960 --> 00:26:02,200 going to be two cells, OK? 420 00:26:02,200 --> 00:26:06,940 So now, paneth cell, another cell. 421 00:26:06,940 --> 00:26:08,780 Here the two daughter cells. 422 00:26:08,780 --> 00:26:11,170 Here's the paneth cell. 423 00:26:11,170 --> 00:26:14,800 The paneth cell is still secreting this Wnt signal. 424 00:26:14,800 --> 00:26:17,110 So you have Wnt getting secreted. 425 00:26:17,110 --> 00:26:19,330 And it's going to signal to its neighbor. 426 00:26:19,330 --> 00:26:21,940 But this cell is starting to get farther and farther 427 00:26:21,940 --> 00:26:24,070 away from that signal, right? 428 00:26:24,070 --> 00:26:26,680 So you can imagine this is happening right here 429 00:26:26,680 --> 00:26:28,840 in the tissue, where this cell is 430 00:26:28,840 --> 00:26:31,990 at the boundary of the niche, OK? 431 00:26:31,990 --> 00:26:34,720 So this cell that gets pushed out of the niche 432 00:26:34,720 --> 00:26:44,140 is going to start to differentiate, OK? 433 00:26:44,140 --> 00:26:48,130 Because it's no longer seeing the signal, OK? 434 00:26:48,130 --> 00:26:50,710 So it's the lack of the Wnt signal 435 00:26:50,710 --> 00:26:53,530 which tells cells basically that they 436 00:26:53,530 --> 00:26:56,620 should start differentiating into the various cell 437 00:26:56,620 --> 00:26:58,160 types of the gut. 438 00:26:58,160 --> 00:27:00,880 But the cells that are stuck at the base of the crypt, 439 00:27:00,880 --> 00:27:05,360 down with the paneth cells, are still getting the Wnt signal. 440 00:27:05,360 --> 00:27:12,730 And so they remain an intestinal stem cell, OK? 441 00:27:12,730 --> 00:27:15,910 So here is just a diagram showing you part of that. 442 00:27:15,910 --> 00:27:19,150 So the niche is down here, where you have the stem cells. 443 00:27:19,150 --> 00:27:21,760 The paneth cells would be some of these blue cells 444 00:27:21,760 --> 00:27:22,720 at the base. 445 00:27:22,720 --> 00:27:27,100 But there are also other cells below the epithelial lining 446 00:27:27,100 --> 00:27:31,630 known as stromal cells that are also secreting Wnt. 447 00:27:31,630 --> 00:27:34,210 And so this compartment down here 448 00:27:34,210 --> 00:27:37,720 has high Wnt ligan activity. 449 00:27:37,720 --> 00:27:42,130 And that tells cells that remain here to stay stem cells. 450 00:27:42,130 --> 00:27:43,960 But the cells that are getting pushed up 451 00:27:43,960 --> 00:27:47,170 and moving up towards the lumen, they no longer 452 00:27:47,170 --> 00:27:48,680 receive this signal. 453 00:27:48,680 --> 00:27:52,300 And so they are going to start to differentiate, OK? 454 00:27:52,300 --> 00:27:56,320 So you can think of this system as almost a conveyor 455 00:27:56,320 --> 00:27:59,320 belt. There's a conveyor belt-like movement of cells 456 00:27:59,320 --> 00:28:02,610 from the base of the crypt up towards the tip of the villis, 457 00:28:02,610 --> 00:28:03,310 OK? 458 00:28:03,310 --> 00:28:06,610 And when the cells move away from the niche cells, 459 00:28:06,610 --> 00:28:09,940 then they no longer have the self-renewal signal. 460 00:28:09,940 --> 00:28:12,130 And therefore, they go on to differentiate. 461 00:28:18,560 --> 00:28:19,060 OK. 462 00:28:19,060 --> 00:28:20,510 We'll go back for now. 463 00:28:20,510 --> 00:28:21,010 All right. 464 00:28:21,010 --> 00:28:25,150 Now, I want to tell you a little bit about this signal, Wnt, 465 00:28:25,150 --> 00:28:28,990 because it's something that's come up before in the lecture, 466 00:28:28,990 --> 00:28:30,830 even though you might not know it. 467 00:28:30,830 --> 00:28:34,270 So Wnt is a ligand. 468 00:28:34,270 --> 00:28:37,180 So it functions much like a growth factor. 469 00:28:37,180 --> 00:28:40,540 This is a protein that is secreted from the cell, 470 00:28:40,540 --> 00:28:43,630 and then binds to receptors on other cells, 471 00:28:43,630 --> 00:28:48,010 and induces signaling events in those cells, OK? 472 00:28:48,010 --> 00:28:49,780 And Wnt stands for-- 473 00:28:49,780 --> 00:28:54,910 the W stands for wingless, OK? 474 00:28:54,910 --> 00:28:58,120 So you remember from earlier in the semester, 475 00:28:58,120 --> 00:29:04,180 wingless was identified as a mutant 476 00:29:04,180 --> 00:29:09,220 that disrupts the formation of wings in the fly, OK? 477 00:29:09,220 --> 00:29:14,920 So one of the places where these genes were discovered 478 00:29:14,920 --> 00:29:16,330 is in the fly. 479 00:29:16,330 --> 00:29:23,230 The nt of Wnt comes from int 1, which 480 00:29:23,230 --> 00:29:28,540 stands for the integration of mouse mammary virus 1. 481 00:29:28,540 --> 00:29:31,000 Sorry, that's a little bit more of a mouthful. 482 00:29:31,000 --> 00:29:34,015 The integration of mouse-- 483 00:29:36,850 --> 00:29:43,460 actually, sorry, mouse mammary tumor virus 1. 484 00:29:43,460 --> 00:29:44,920 I forgot the tumor part of it. 485 00:29:52,590 --> 00:29:53,500 OK. 486 00:29:53,500 --> 00:29:56,740 So the W in Wnt is from wingless. 487 00:29:56,740 --> 00:30:01,060 The nt in Wnt is from int 1, OK? 488 00:30:01,060 --> 00:30:06,190 And so as you can see, there are two different systems 489 00:30:06,190 --> 00:30:09,210 where this type of gene was discovered. 490 00:30:09,210 --> 00:30:11,840 They are very disparate from each other. 491 00:30:11,840 --> 00:30:16,090 One was in a developmental mutant, in the fruit fly. 492 00:30:16,090 --> 00:30:21,070 The other was in a mouse system, where 493 00:30:21,070 --> 00:30:24,070 the integration of the virus caused over-expression 494 00:30:24,070 --> 00:30:28,420 of Wnt, which caused it as tumor genesis, OK? 495 00:30:28,420 --> 00:30:32,200 So these disparate systems led to the identification 496 00:30:32,200 --> 00:30:35,350 of this Wnt molecule. 497 00:30:35,350 --> 00:30:39,310 And this is a defining member of a signaling pathway 498 00:30:39,310 --> 00:30:42,170 that regulates stem cell renewal. 499 00:30:42,170 --> 00:30:44,800 And I just want to briefly go through the logic 500 00:30:44,800 --> 00:30:47,980 of the signaling pathway, because I want 501 00:30:47,980 --> 00:30:50,860 you to get a sense that not all signaling pathways are 502 00:30:50,860 --> 00:30:52,840 like Ras-MAP kinase, but there can be 503 00:30:52,840 --> 00:30:55,450 different regulatory logic, OK? 504 00:30:55,450 --> 00:30:59,380 So what's the regulatory logic of this pathway? 505 00:31:03,080 --> 00:31:11,270 So the regulatory logic is shown in this cartoon. 506 00:31:11,270 --> 00:31:13,570 And I'm going to start with a cell that 507 00:31:13,570 --> 00:31:15,970 does not see Wnt ligand. 508 00:31:15,970 --> 00:31:19,270 So that would be the case on the left here. 509 00:31:19,270 --> 00:31:20,980 So if there's no Wnt ligand-- 510 00:31:20,980 --> 00:31:24,110 I want you to focus on what's going on here-- 511 00:31:24,110 --> 00:31:28,420 there's a complex that's present in the cytoplasm of the cell. 512 00:31:28,420 --> 00:31:30,310 And what it's doing is it's destroying 513 00:31:30,310 --> 00:31:33,700 this beta-catenin protein, OK? 514 00:31:33,700 --> 00:31:36,880 So what beta-catenin is-- 515 00:31:36,880 --> 00:31:41,590 among other things, it's a transcriptional coactivator. 516 00:31:41,590 --> 00:31:43,345 So it's basically a transcription factor. 517 00:31:48,580 --> 00:31:52,780 So it works with another protein to regulate the expression 518 00:31:52,780 --> 00:31:56,720 of certain genes, OK? 519 00:31:56,720 --> 00:32:01,180 And in the absence of Wnt, this beta-catenin transcription 520 00:32:01,180 --> 00:32:07,090 factor is destroyed and is not able to get into the nucleus, 521 00:32:07,090 --> 00:32:09,460 OK? 522 00:32:09,460 --> 00:32:19,000 So if there's no Wnt, then beta-catenin is destroyed. 523 00:32:22,390 --> 00:32:24,310 And it's destroyed using a system 524 00:32:24,310 --> 00:32:26,770 that I introduced in Monday's lecture, which 525 00:32:26,770 --> 00:32:31,030 is regulated proteolysis by polyubiquitination, OK? 526 00:32:31,030 --> 00:32:32,390 So the first real-- 527 00:32:35,050 --> 00:32:42,010 so you have regulated proteolysis 528 00:32:42,010 --> 00:32:43,790 by polyubiquitination. 529 00:32:47,200 --> 00:32:50,500 So the way this works, as seen here, 530 00:32:50,500 --> 00:32:56,620 is that beta-catenin is bound by this complex. 531 00:32:56,620 --> 00:33:00,250 And there's a kinase that phosphorylates beta-catenin. 532 00:33:00,250 --> 00:33:02,680 And then the phosphorylated beta-catenin 533 00:33:02,680 --> 00:33:05,410 recruits this E3 ubiquitin ligase, which 534 00:33:05,410 --> 00:33:08,320 polyubiquitinates it, OK? 535 00:33:08,320 --> 00:33:10,670 So that leads to the destruction of beta-catenin 536 00:33:10,670 --> 00:33:14,230 in the absence of a Wnt signal. 537 00:33:14,230 --> 00:33:17,020 But when Wnt ligand is around, this 538 00:33:17,020 --> 00:33:20,980 leads to the disassembly of this complex, which is known 539 00:33:20,980 --> 00:33:23,110 as the destruction complex. 540 00:33:23,110 --> 00:33:26,410 And that leads to beta-catenin accumulating. 541 00:33:26,410 --> 00:33:29,230 And once it accumulates, it goes into the nucleus 542 00:33:29,230 --> 00:33:32,710 and starts changing gene expression, OK? 543 00:33:32,710 --> 00:33:45,720 So in the presence of Wnt, beta-catenin is nuclear. 544 00:33:45,720 --> 00:33:48,640 And that's where it needs to be, if it's going to regulate 545 00:33:48,640 --> 00:33:51,550 gene expression, OK? 546 00:33:51,550 --> 00:33:54,580 So what you see is the logic of this pathway 547 00:33:54,580 --> 00:33:57,880 is you have a double negative, where 548 00:33:57,880 --> 00:34:03,125 you have a complex, which is known as the destruction 549 00:34:03,125 --> 00:34:03,625 complex. 550 00:34:08,219 --> 00:34:10,780 And it includes this gene, APC, which we're 551 00:34:10,780 --> 00:34:12,790 going to talk about on Friday. 552 00:34:12,790 --> 00:34:15,909 This destruction complex is inhibiting beta-catenin 553 00:34:15,909 --> 00:34:16,960 by destroying it. 554 00:34:21,420 --> 00:34:26,860 And the way that Wnt induces beta-catenin activation 555 00:34:26,860 --> 00:34:29,830 is by inhibiting the inhibitor. 556 00:34:29,830 --> 00:34:33,889 So Wnt inhibits the destruction complex, 557 00:34:33,889 --> 00:34:37,150 which then stabilizes beta-catenin and allows 558 00:34:37,150 --> 00:34:39,489 it to go to the nucleus, OK? 559 00:34:39,489 --> 00:34:42,280 So the other piece of the logic here 560 00:34:42,280 --> 00:34:48,520 is you have inhibition of an inhibitor 561 00:34:48,520 --> 00:34:50,487 to activate beta-catenin. 562 00:34:55,469 --> 00:34:57,385 Any questions on the pathway? 563 00:35:04,210 --> 00:35:04,710 OK. 564 00:35:04,710 --> 00:35:11,040 So now that we have our intestinal stem cells 565 00:35:11,040 --> 00:35:16,710 and we have a way, by increasing Wnt in this compartment, 566 00:35:16,710 --> 00:35:22,500 to maintain the intestinal stem cells through self-renewal, now 567 00:35:22,500 --> 00:35:25,080 we have to talk about the compensatory 568 00:35:25,080 --> 00:35:28,260 mechanism of death, which allows this tissue 569 00:35:28,260 --> 00:35:29,670 to maintain homeostasis. 570 00:35:34,930 --> 00:35:35,430 OK. 571 00:35:35,430 --> 00:35:39,870 So death-- in this case, death is going to be useful. 572 00:35:39,870 --> 00:35:45,430 And the process of death is called apoptosis. 573 00:35:48,710 --> 00:35:51,600 And apoptosis is Greek for falling off. 574 00:36:01,430 --> 00:36:03,510 And that's essentially what these cells 575 00:36:03,510 --> 00:36:07,920 are doing, because the cells, as they 576 00:36:07,920 --> 00:36:11,280 move from the base of the crypt up towards the lumen-- 577 00:36:11,280 --> 00:36:12,870 eventually, they're going to fall off 578 00:36:12,870 --> 00:36:16,630 into the lumen of the intestine. 579 00:36:16,630 --> 00:36:19,190 So again, I'll draw. 580 00:36:19,190 --> 00:36:20,205 Here's a villus. 581 00:36:20,205 --> 00:36:21,080 This is now a villus. 582 00:36:37,840 --> 00:36:40,980 And so what happens is, at the tip of the villus, 583 00:36:40,980 --> 00:36:45,060 cells are going to be shed from the lining of the epithelium 584 00:36:45,060 --> 00:36:46,260 into the lumen. 585 00:36:46,260 --> 00:36:49,320 The lumen is up here. 586 00:36:49,320 --> 00:36:50,820 This is the villus. 587 00:36:50,820 --> 00:36:53,340 And the cells are going to shed off into the lumen 588 00:36:53,340 --> 00:36:57,750 and be removed from the organ system, OK? 589 00:36:57,750 --> 00:37:06,060 So cells are shed into the lumen here, OK? 590 00:37:06,060 --> 00:37:09,420 And this is going to balance the renewal 591 00:37:09,420 --> 00:37:17,040 at the base of the crypts such that there's homeostasis. 592 00:37:17,040 --> 00:37:19,290 So I just-- the movie I was showing you 593 00:37:19,290 --> 00:37:22,590 at the beginning of class was a movie showing you 594 00:37:22,590 --> 00:37:25,950 what happens to a cell undergoing apoptosis. 595 00:37:25,950 --> 00:37:29,700 So in this case, the cell is binucleate and unhappy. 596 00:37:29,700 --> 00:37:34,410 And then you're going to see that it basically explodes, OK? 597 00:37:34,410 --> 00:37:36,970 So that's a cell undergoing apoptosis. 598 00:37:36,970 --> 00:37:40,950 But you see that there is a clear change in cell morphology 599 00:37:40,950 --> 00:37:44,190 and physiology associated with this. 600 00:37:44,190 --> 00:37:46,590 And I just want to point out that this is also something 601 00:37:46,590 --> 00:37:49,450 that we talked about earlier in the course. 602 00:37:49,450 --> 00:37:53,250 And we talked about experiments, a genetic screen that 603 00:37:53,250 --> 00:37:56,340 led to the identification of the pathway that 604 00:37:56,340 --> 00:37:58,590 regulates apoptosis. 605 00:37:58,590 --> 00:38:00,840 And that was done by Robert Horvitz. 606 00:38:00,840 --> 00:38:05,780 Much of it was done by Robert Horvitz in his lab here at MIT. 607 00:38:05,780 --> 00:38:10,680 And for that work, Robert Horvitz, in addition to 608 00:38:10,680 --> 00:38:15,210 his colleagues, won the 2002 Nobel Prize. 609 00:38:15,210 --> 00:38:17,040 So you'll recall this is something 610 00:38:17,040 --> 00:38:20,100 we talked about in the context of a genetic screen. 611 00:38:20,100 --> 00:38:21,720 But this is something that's-- 612 00:38:21,720 --> 00:38:25,140 this is what it's doing in your intestine system. 613 00:38:25,140 --> 00:38:29,880 It's balancing renewal so that you have homeostasis. 614 00:38:29,880 --> 00:38:36,170 So during apoptosis, a cell goes through a series of changes. 615 00:38:36,170 --> 00:38:38,490 First-- or what happens eventually 616 00:38:38,490 --> 00:38:42,300 is the nucleus becomes fragmented and chromosomal DNA 617 00:38:42,300 --> 00:38:43,560 even gets fragmented. 618 00:38:43,560 --> 00:38:45,600 It gets chopped up. 619 00:38:45,600 --> 00:38:49,710 And also, the plasma membrane also 620 00:38:49,710 --> 00:38:54,420 starts to bleb and fragment such that it breaks up 621 00:38:54,420 --> 00:38:58,470 into what are known as these apoptotic bodies, OK? 622 00:38:58,470 --> 00:39:01,590 And so you can think of these apoptotic bodies 623 00:39:01,590 --> 00:39:06,060 as bite-sized pieces of cell that neighboring 624 00:39:06,060 --> 00:39:11,070 phagocytic cells can eat up and remove them from the body, OK? 625 00:39:11,070 --> 00:39:13,992 So in this case, the cells are being shed into the lumen. 626 00:39:13,992 --> 00:39:15,450 So they don't need to get eaten up, 627 00:39:15,450 --> 00:39:18,900 because they're just going to go out of the digestive tract. 628 00:39:27,160 --> 00:39:30,310 So there are-- cells have numerous ways 629 00:39:30,310 --> 00:39:34,270 to activate this apoptosis process. 630 00:39:34,270 --> 00:39:39,070 I'm going to tell you about two types of signals 631 00:39:39,070 --> 00:39:44,000 that regulate whether or not a cell undergoes apoptosis. 632 00:39:49,990 --> 00:39:53,410 The first is that there can be a signal that basically tells 633 00:39:53,410 --> 00:39:58,480 the cell to kill itself, OK? 634 00:39:58,480 --> 00:40:00,580 So you can think of this as a kill signal. 635 00:40:03,920 --> 00:40:07,060 And one type of way to activate this signal 636 00:40:07,060 --> 00:40:10,930 is if the DNA is irreparably damaged. 637 00:40:10,930 --> 00:40:15,550 So if there is a high level of DNA damage, 638 00:40:15,550 --> 00:40:19,870 this induces a signaling process in the cell. 639 00:40:19,870 --> 00:40:23,740 And one of the results of that signal-- 640 00:40:23,740 --> 00:40:26,290 in addition to regulating the cell cycle, 641 00:40:26,290 --> 00:40:29,770 if the DNA damage is great enough, 642 00:40:29,770 --> 00:40:32,490 it will induce an apoptotic signal. 643 00:40:32,490 --> 00:40:37,480 And it will activate the pathway that the Horvitz lab elucidated 644 00:40:37,480 --> 00:40:39,940 in the worm, OK? 645 00:40:39,940 --> 00:40:41,180 So there's a signal. 646 00:40:41,180 --> 00:40:45,430 And that leads to apoptosis and death. 647 00:40:50,110 --> 00:40:54,220 Another type of signal that's critically important for tissue 648 00:40:54,220 --> 00:40:57,290 homeostasis and determining whether or not cells live 649 00:40:57,290 --> 00:41:01,690 or die is a survival signal. 650 00:41:01,690 --> 00:41:03,640 So there are cell survival signals. 651 00:41:08,950 --> 00:41:13,540 And many of the growth factors, such as EGF which you've heard 652 00:41:13,540 --> 00:41:14,410 about-- 653 00:41:14,410 --> 00:41:17,740 in addition to inducing proliferation, 654 00:41:17,740 --> 00:41:23,230 these growth factors also tell the cell not to die, OK? 655 00:41:23,230 --> 00:41:25,285 So these could be growth factors. 656 00:41:30,670 --> 00:41:35,830 And what these cell survival signals do 657 00:41:35,830 --> 00:41:37,870 is they repress apoptosis. 658 00:41:41,890 --> 00:41:45,460 And so you can think of it where you have 659 00:41:45,460 --> 00:41:49,030 a cell constantly needs to be communicated to. 660 00:41:49,030 --> 00:41:52,660 And it needs to be told don't die, 661 00:41:52,660 --> 00:41:55,660 don't die, don't die, don't die. 662 00:41:55,660 --> 00:41:58,330 And then if you remove that signal, 663 00:41:58,330 --> 00:42:00,340 it won't be getting that information anymore. 664 00:42:00,340 --> 00:42:03,430 And it can undergo apoptosis, OK? 665 00:42:03,430 --> 00:42:06,760 So if we were to remove this signal, 666 00:42:06,760 --> 00:42:09,400 you remove the brakes on apoptosis. 667 00:42:09,400 --> 00:42:12,520 And the cell will undergo cell death, OK? 668 00:42:12,520 --> 00:42:17,350 So this ensures that you don't have a cell just kind 669 00:42:17,350 --> 00:42:19,750 of like going on and doing its own thing, 670 00:42:19,750 --> 00:42:22,360 because cells, in order to live, often 671 00:42:22,360 --> 00:42:25,960 need to have some sort of signal from another cell that 672 00:42:25,960 --> 00:42:27,170 tells them to live. 673 00:42:27,170 --> 00:42:31,090 And so there's some coordination between cells such 674 00:42:31,090 --> 00:42:33,400 that you don't have cells rampantly 675 00:42:33,400 --> 00:42:34,675 dividing out of control. 676 00:42:40,670 --> 00:42:42,700 Now, the reason we're doing this right 677 00:42:42,700 --> 00:42:45,460 before we talk about cancer on Friday 678 00:42:45,460 --> 00:42:48,220 is because everything that I'm telling you 679 00:42:48,220 --> 00:42:52,450 is really essential to understand how a tumor is 680 00:42:52,450 --> 00:42:55,380 formed in an organ system, OK? 681 00:42:55,380 --> 00:42:57,970 And I want to end the lecture by just planting 682 00:42:57,970 --> 00:43:01,210 a seed of an idea in your heads before we move on 683 00:43:01,210 --> 00:43:03,940 to talk about cancer on Friday. 684 00:43:03,940 --> 00:43:07,390 And I want you to think about the organization 685 00:43:07,390 --> 00:43:13,060 of this system, where you have stem cells undergoing renewal. 686 00:43:13,060 --> 00:43:17,050 And then the stem cells are just a small fraction 687 00:43:17,050 --> 00:43:19,120 of the cells in the system. 688 00:43:19,120 --> 00:43:21,070 And they're dividing slowly, OK? 689 00:43:21,070 --> 00:43:22,780 So let's think about the stem cells. 690 00:43:25,880 --> 00:43:29,395 The DNA on the stem cells, these are dividing slowly. 691 00:43:33,490 --> 00:43:35,230 And because they're dividing slowly, 692 00:43:35,230 --> 00:43:37,060 they're not going to-- their DNA is not 693 00:43:37,060 --> 00:43:40,330 going to accumulate as many mutations. 694 00:43:40,330 --> 00:43:43,060 So there is going to be fewer mutations. 695 00:43:46,010 --> 00:43:47,630 But these are the cells, and this 696 00:43:47,630 --> 00:43:53,480 is the genomic DNA that is going to stay with the organ, OK? 697 00:43:53,480 --> 00:43:57,250 So the stem cells are like the crown jewels of the organ. 698 00:43:57,250 --> 00:44:00,950 This is the material the organ wants to protect, 699 00:44:00,950 --> 00:44:03,380 because it's what's going to be lasting 700 00:44:03,380 --> 00:44:08,060 in the organ the entire lifetime of the organism, OK? 701 00:44:08,060 --> 00:44:11,750 So you get slow division here and self-renewal. 702 00:44:11,750 --> 00:44:15,260 And this cell will stay with the organ. 703 00:44:15,260 --> 00:44:18,200 But then where most of the mitosis and cell division 704 00:44:18,200 --> 00:44:20,990 happens and replication happens, it 705 00:44:20,990 --> 00:44:25,640 leads to an expansion of cells that all differentiate. 706 00:44:25,640 --> 00:44:27,410 And because the cells all differentiate, 707 00:44:27,410 --> 00:44:31,580 they will all eventually die and get removed from the organ, OK? 708 00:44:31,580 --> 00:44:36,530 And this is termed transient amplification. 709 00:44:36,530 --> 00:44:41,270 So when there's transient amplification of one 710 00:44:41,270 --> 00:44:44,400 of the daughters of this stem cell, 711 00:44:44,400 --> 00:44:46,025 this is where there's rapid division. 712 00:44:49,140 --> 00:44:52,180 And where there is rapid replication and division, 713 00:44:52,180 --> 00:44:54,580 this is where you can get the most mutations. 714 00:44:58,390 --> 00:45:00,910 But from the standpoint of cancer, 715 00:45:00,910 --> 00:45:02,800 that doesn't really matter, right? 716 00:45:02,800 --> 00:45:05,320 Because in order to have a tumor, 717 00:45:05,320 --> 00:45:07,630 the cells have to stay in the body. 718 00:45:07,630 --> 00:45:09,490 And so all of these cells are going 719 00:45:09,490 --> 00:45:11,740 to undergo programmed cell death, 720 00:45:11,740 --> 00:45:14,230 and then be shed into the lumen of the intestine 721 00:45:14,230 --> 00:45:18,190 and removed from the organism entirely, OK? 722 00:45:18,190 --> 00:45:23,020 And so this is actually one important way 723 00:45:23,020 --> 00:45:28,180 that our organs and our bodies prevent tumors from happening, 724 00:45:28,180 --> 00:45:32,470 because the cell type that is going to remain in our body 725 00:45:32,470 --> 00:45:36,460 is the one that's protected from accumulating mutations, OK? 726 00:45:36,460 --> 00:45:38,770 And we'll come back to this on Friday. 727 00:45:38,770 --> 00:45:40,660 And so I will see you on Friday. 728 00:45:40,660 --> 00:45:45,480 And we'll talk about cancer on Friday.